研究者総覧

眞嶋 浩聡 (マシマ ヒロサト)

  • 総合医学第1講座 教授
Last Updated :2021/09/22

研究者情報

学位

  • 医学博士(東京大学)

ホームページURL

J-Global ID

研究キーワード

  • 分化   膵内分泌細胞   AR42J細胞   IRF-2   急性膵炎   アクチビンA   S100   外分泌   胆道学   タイトジャンクション(TJ)   AR42J   膵腺房細胞   膵   mRNA Differential Display   ヒト肝癌細胞   アネキシン   SNARE   JAM-1   アクチビン受容体   膵臓学   カルシウム   RB蛋白   分化誘導   インスリン   膵β細胞   インバースアゴニスト   アクチビン   遺伝子   遺伝子因子大腸   分子細胞生物学   潰瘍性大腸炎   肝臓   膵臓   molecular biology   gut   stomach   endocrine   exocrine   pancreas   

研究分野

  • ライフサイエンス / 消化器内科学
  • ライフサイエンス / 代謝、内分泌学
  • ライフサイエンス / 消化器内科学

経歴

  • 2015年04月 - 現在  自治医科大学附属さいたま医療センター教授
  • 2009年05月 - 2015年03月  秋田大学医学部講師

学歴

  •         - 1987年   東京大学   医学部

所属学協会

  • 日本膵臓学会   日本消化器内視鏡学会   日本消化器病学会   日本内科学会   

研究活動情報

論文

  • Sekine M, Miyatani H, Matsumoto K, Kashima H, Koito Y, Miura T, Takahashi Y, Tsuboi R, Ishii T, Fujiwara J, Uehara T, Urayoshi S, Yuhashi K, Asano T, Sagihara N, Matsumoto S, Mashima H
    Internal medicine (Tokyo, Japan) 57 18 2663 - 2668 2018年09月 [査読有り][通常論文]
  • 急性膵炎発症・進展における細胞内小胞輸送の役割
    高橋健一, 眞嶋浩聡, 大西洋英
    膵臓 33 4 723 - 729 2018年08月 [査読有り][招待有り]
  • Miyatani H, Mashima H, Sekine M, Matsumoto S
    Scientific reports 8 1 9951  2018年07月 [査読有り][通常論文]
  • 関根 匡成, 松本 吏弘, 浅野 岳晴, 鷺原 規喜, 宮谷 博幸, 眞嶋 浩聡
    臨床消化器内科 33 7 761 - 764 (株)日本メディカルセンター 2018年05月 [査読無し][通常論文]
  • Rumiko Tsuboi, Takeharu Asano, Katsuhiko Matsuura, Shinichi Asabe, Hirosato Mashima
    Chinese Medical Journal 131 8 999 - 1000 2018年04月 [査読有り][通常論文]
  • Mashima H, Watanabe N, Sekine M, Matsumoto S, Asano T, Yuhashi K, Sagihara N, Urayoshi S, Uehara T, Fujiwara J, Ishii T, Tsuboi R, Miyatani H, Ohnishi H
    Biochemistry and biophysics reports 13 93 - 98 2018年03月 [査読有り][通常論文]
     
    Intestinal homeostasis and the coordinated actions of digestion, absorption and excretion are tightly regulated by a number of gastrointestinal hormones. Most of them exert their actions through G-protein-coupled receptors. Recently, we showed that the absence of Gαq/Gα11 signaling impaired the maturation of Paneth cells, induced their differentiation toward goblet cells, and affected the regeneration of the colonic mucosa in an experimental model of colitis. Although an immunohistochemical study showed that Gαq/Gα11 were highly expressed in enterocytes, it seemed that enterocytes were not affected in Int-Gq/G11 double knock-out intestine. Thus, we used an intestinal epithelial cell line to examine the role of signaling through Gαq/Gα11 in enterocytes and manipulated the expression level of Gαq and/or Gα11. The proliferation was inhibited in IEC-6 cells that overexpressed Gαq/Gα11 and enhanced in IEC-6 cells in which Gαq/Gα11 was downregulated. The expression of T-cell factor 1 was increased according to the overexpression of Gαq/Gα11. The expression of Notch1 intracellular cytoplasmic domain was decreased by the overexpression of Gαq/Gα11 and increased by the downregulation of Gαq/Gα11. The relative mRNA expression of Muc2, a goblet cell marker, was elevated in a Gαq/Gα11 knock-down experiment. Our findings suggest that Gαq/Gα11-mediated signaling inhibits proliferation and may support a physiological function, such as absorption or secretion, in terminally differentiated enterocytes.
  • 【オートファジー〜胆膵疾患とのかかわりについて〜】 急性膵炎におけるオートファジーとエンドサイトーシス
    眞嶋 浩聡, 高橋 健一, 大西 洋英
    胆と膵 39 2 139 - 145 医学図書出版(株) 2018年02月 [査読無し][通常論文]
     
    急性膵炎の発症にはトリプシンの異所性活性化やNF-κBの活性化、オートファジー不全、小胞体ストレス、酸化ストレス、細胞内カルシウムシグナル異常などが関与している。オートファジーは老廃物の分解や再利用を通じて細胞の恒常性の維持に寄与するが、膵炎発症時には機能不全が生じ、トリプシンの活性化を生じる。急性膵炎が発症すると外分泌が障害されるが、エキソサイトーシスと表裏一体の関係にあるエンドサイトーシスはオートファジーと類似の機能であり、急性膵炎の発症にも関与している。細胞内の小胞輸送はさまざまなRabタンパク質によって制御されているが、オートファゴソームとエンドソームの膜上に存在するRab7を欠失させた膵臓では、オートファジー不全とエンドソームの成熟過程に障害が生じて、膵炎反応が増悪する。(著者抄録)
  • Matsumoto S, Mashima H
    Biologics : targets & therapy 12 69 - 73 2018年 [査読有り][通常論文]
  • 大腸内視鏡的処置時に鉗子口からの処置具の急な突出を防ぐためのアイデア 処置具カラーマーキング法(「カラーテープ仁丹法」の応用)
    松本 博成, 石田 茂夫, 宮谷 博幸, 眞嶋 浩聡
    埼玉県医学会雑誌 52 1 358 - 361 埼玉県医学会 2017年12月 [査読無し][通常論文]
     
    大腸内視鏡的処置時に鉗子口からの処置具の急な突出を防ぐための装置を開発したので報告した。方法は生検鉗子やポリペクトミー用スネア外筒など処置具に熱収縮性ビニルテープを内視鏡処置管路長より5cm短く設置し、その凹凸と色の変化を利用する処置具カラーマーキング法とした。実際に処置具カラーマーキング法を使用すると、画面に視野を集中する際も処置具のマーカーが視野の片隅に入り、また処置具挿入中の手元でも5cm手前のマーカーを触知することができた。そこから処置具を慎重に挿入することにより急な突出を防止することが可能であった。
  • 関根 匡成, 宮谷 博幸, 眞嶋 浩聡
    Gastroenterological Endoscopy 59 10 2533 - 2534 (一社)日本消化器内視鏡学会 2017年10月 [査読無し][通常論文]
  • Hiroyuki Miyatani, Satohiro Matsumoto, Hirosato Mashima
    Journal of Digestive Diseases 18 10 591 - 597 2017年10月 [査読有り][通常論文]
     
    OBJECTIVE: Suspected sphincter of Oddi dysfunction (SOD) is a well-known risk factor for post-endoscopic retrograde cholangiopancreatography (ERCP) pancreatitis (PEP). The indication of ERCP for suspected SOD patients was very low in Japan compared to other countries. Therefore, the risk of PEP may be different in Japanese SOD patients. The objective of this study was to evaluate the risk of PEP in suspected biliary type SOD in Japan. METHODS: From December 1996 to January 2017, 72 patients were suspected as having biliary type SOD, by questionnaire, liver function tests, hepatobiliary scintigraphy, abdominal ultrasonography, upper gastrointestinal endoscopy, endoscopic ultrasonography and magnetic resonance cholangiopancreatography. Finally, 60 patients who underwent ERCP were included in this study, and the factors associated with PEP were evaluated. RESULTS: The overall PEP rate was 23.3% (n = 14). Diagnostic ERCP alone for SOD did not increase the risk of PEP. The correlation of PEP incidence with pancreatic duct guidewire (PGW) technique and endoscopic sphincterotomy (EST) was indicated in univariate and multivariate analysis. Pancreatic stent placement was a risk in univariate analysis but not in multivariate analysis. CONCLUSIONS: PGW technique and EST for biliary type SOD were important risk factors for PEP. Pancreatic stenting was ineffective for prevention of PEP.
  • Satohiro Matsumoto, Haruna Kawamura, Takeshi Nishikawa, Noriyoshi Sagihara, Hiroyuki Miyatani, Hirosato Mashima
    Clinical and Experimental Gastroenterology 10 249 - 258 2017年09月 [査読有り][通常論文]
     
    Background and aims: At Saitama Medical Center, for remission induction in active ulcerative colitis (UC) patients with endoscopic evidence of severe disease, we tend to preferentially use tacrolimus (TAC) over anti-tumor necrosis factor (TNF)-a agents. We conducted this study to evaluate the validity of our therapeutic strategies. Patients and methods: This retrospective study was conducted in 52 steroid-refractory active UC patients with a Clinical Activity Index (CAI) score of ≥7 who were receiving remission induction therapy with TAC or anti-TNF-α agents. The patients were divided into a TAC treatment group (TAC group, n = 29) and an anti-TNF-α agent treatment group (anti-TNF group, n = 23). The CAI, Ulcerative Colitis Endoscopic Index of Severity (UCEIS) and incidence of events (relapse, hospitalization and surgery) were retrospectively analyzed. Results: At treatment initiation, the CAI score was 12.6 in the TAC group and 11.5 in the anti-TNF group (P = 0.09), while the corresponding values of the UCEIS were 6.5 and 5.1, respectively (P = 0.0035). The clinical remission rate at 12 weeks was 55% (65% when only the subgroup that received rapid induction therapy was included in the analysis) in the TAC group and 57% in the anti-TNF group, with no significant difference. The cumulative event-free rates at 1, 6 and 12 months were 65.5%, 39.4%, and 39.4%, respectively, in the TAC group and 95.7%, 77.2% and 71.7%, respectively, in the anti-TNF group (P = 0.0037). Conclusion: Rapid induction therapy with TAC tended to be selected for active UC patients with endoscopic evidence of severe disease, and the present study supported the validity of this therapeutic approach. However, transition to the remission-maintenance phase was more favorable in the anti-TNF group.
  • Satohiro Matsumoto, Hirosato Mashima
    INTERNATIONAL JOURNAL OF COLORECTAL DISEASE 32 6 831 - 837 2017年06月 [査読有り][通常論文]
     
    Although endoscopic submucosal dissection (ESD) is becoming the mainstay of the treatment strategies, rather than surgical treatment, for colorectal tumors extending to the dentate line, ESD is technically more difficult. This study was aimed at assessing the usefulness of ESD for the treatment of colorectal tumors extending to the dentate line. This study included 531 patients with colorectal tumors who underwent colorectal ESD between 2008 and 2015. They were divided into three groups: rectal tumors extending to the dentate line (anorectal group), those not extending to the dentate line (proximal rectal group), and colonic tumors (colonic group), and a retrospective comparative analysis was carried out. Of the total patients, 18 (3.4%) had lesions extending to the dentate line area. The procedure times were 103.4 +/- 84.0, 80.4 +/- 64.3, and 71.8 +/- 52.3 min, respectively (P = 0.0318). All the patients in the anorectal group were operated by operators who had performed at least 20 colorectal ESDs (P < 0.0001). No significant difference among the three groups was found in the en bloc resection rate, complete resection rate, or curative resection rate. Although no significant difference in the incidence of perforation was observed among the three groups, intraoperative bleeding was observed in 61% of the patients in the anorectal group (P < 0.0001). ESD is an effective treatment strategy for colorectal tumors extending to the dentate line. However, it seems that anorectal ESD, which is technically more difficult than colorectal ESD, should be performed by operators with ample experience in performing ESD.
  • Kenichi Takahashi, Hirosato Mashima, Kouichi Miura, Daichi Maeda, Akiteru Goto, Takashi Goto, Ge-Hong Sun-Wada, Yoh Wada, Hirohide Ohnishi
    SCIENTIFIC REPORTS 7 1 2817  2017年06月 [査読有り][通常論文]
     
    Although aberrations of intracellular vesicle transport systems towards lysosomes including autophagy and endocytosis are involved in the onset and progression of acute pancreatitis, the molecular mechanisms underlying such aberrations remain unclear. The pathways of autophagy and endocytosis are closely related, and Rab7 plays crucial roles in both. In this study, we analyzed the function of Rab7 in acute pancreatitis using pancreas-specific Rab7 knockout (Rab7(Delta pan)) mice. In Rab7(Delta pan) pancreatic acinar cells, the maturation steps of both endosomes and autophagosomes were deteriorated, and the lysosomal functions were affected. In experimental models of acute pancreatitis, the histopathological severity, serum amylase concentration and intra-pancreatic trypsin activity were significantly higher in Rab7(Delta pan) mice than in wild-type mice. Furthermore, the autophagy process was blocked in Rab7(Delta pan) pancreas compared with wild-type mice. In addition, larger autophagic vacuoles that colocalize with early endosome antigen 1 (EEA1) but not with lysosomal-associated membrane protein (LAMP)-1 were much more frequently formed in Rab7(Delta pan) pancreatic acinar cells. Accordingly, Rab7 deficiency exacerbates the severity of acute pancreatitis by impairing the autophagic and endocytic pathways toward lysosomes.
  • Haruna Kawamura, Satohiro Matsumoto, Noriyuki Nakamura, Hiroyuki Miyatani, Hirosato Mashima
    American Journal of Case Reports 18 405 - 409 2017年04月 [査読有り][通常論文]
     
    Objective: Unusual setting of medical care Background: Tacrolimus is reportedly effective for the treatment of refractory ulcerative colitis (UC). At our hospital, there has been an increase in the number of patients, including elderly patients, with refractory UC treated with tacrolimus. Here, we review the data from 5 patients with elderly-onset UC treated with tacrolimus as remission induction therapy. Case Report: The subjects were 5 patients ≥65 years of age with refractory UC who had received oral tacrolimus as remission induction therapy between 2009 and 2014 (3 men and 2 women median age at onset, 75 years). At the start of the tacrolimus treatment, the median duration of disease was 3 months, and the type of UC was total colitis in 4 cases, and left-sided colitis in 1 case. The drugs used concomitantly at the start of tacrolimus treatment were mesalazine (5 cases) and an immunomodulator drug (1 case). Standard induction therapy (0.05 mg/kg/day) was used in 2 patients and rapid induction therapy (0.1 mg/kg/day) was used in the remaining 3 patients. One week after the start of treatment, the blood trough concentrations of tacrolimus were over the target level of 15 mg/mL in 4 patients. The clinical activity index values on day 0 and day 14 were 10.6±2.1 and 7.6±3.4, respectively. The ulcerative colitis endoscopic index of severity in the remaining 3 patients, after excluding the 2 patients who required colectomy within 14 days after the start of tacrolimus therapy, was 7.3±1.0 before the start of the tacrolimus treatment, improving to 4.5±0.5 on day 14. Subsequently, 1 of these 3 patients was also judged to need surgery due to symptom exacerbation, while complete remission was maintained in the other 2 patients. Conclusions: In elderly-onset refractory UC patients, tacrolimus appears to be effective as remission induction therapy. However, since tacrolimus concentrations in the blood can rise easily in elderly patients, frequent monitoring of the drug concentrations and dosage adjustments are necessary.
  • Daisuke Suzuki, Satohiro Matsumoto, Hirosato Mashima
    American Journal of Case Reports 18 304 - 307 2017年03月 [査読有り][通常論文]
     
    Objective: Unusual setting of medical care Background: Serrated polyposis syndrome (SPS) is characterized by numerous hyperplastic polyps and sessile serrated ad-enoma/polyp (SSA/P) in the large intestine. SSA/P is known to transform into malignant lesions through the serrated pathway instead of the adenoma-carcinoma sequence. Early diagnosis with lower gastrointestinal endoscopy and early treatment are now considered to be essential. Case Report: We had an experience with a case of SPS to which endoscopic treatment was applied in multiple sessions. Endoscopic treatment was performed for 16 lesions in total, and the pathological findings were SSA/P for 15 and adenoma for the other lesion. We intend to continue performing endoscopic surveillance for any newly developing lesions. Conclusions: SPS has a potential for malignant transformation, and issues, such as long-term prognosis and optimal therapeutic strategies, await resolution. However, multiple endoscopic treatments are useful for cases with lesions that are controllable employing this modality.
  • Haruka Otake, Satohiro Matsumoto, Hirosato Mashima
    MEDICINE 96 16 e6635  2017年 [査読有り][通常論文]
     
    Although biologics are important inflammatory bowel disease therapies, loss of response (LOR) remains problematic. We evaluated LOR to biologics in our Crohn disease (CD) patients receiving biologics. Of 137 biologic-treated CD patients, 68 continuously receiving the same biologic type for at least 1 year were divided into 2 groups: infliximab (IFX) (n= 39) and adalimumab (ADA) (n= 29). Clinical courses were compared at biologic introduction and at 1 year. Both groups were retrospectively analyzed for LOR at and beyond 1 year after biologic introduction (study endpoint). Patients were then divided into LOR and non-LOR groups to identify factors predicting LOR. At 1 year after biologic introduction, decreases in CD activity index were 94 +/- 105 in the IFX and 102 +/- 89 in the ADA group, not significantly different. Blood test data did not differ between these groups. LOR occurred in 14 IFX and 5 ADA group patients. Event-free rates at 5 years after biologic introduction were 62% in the IFX and 61% in the ADA group. Patients achieving clinical remission 1 year after biologic introduction accounted for 69% of the IFX and 90% of the ADA group, while respective rates of secondary LOR at 5 years were 32% and 26%. C-reactive protein (CRP) at biologic introduction (odds ratio [OR], 1.5; 95% confidence interval [CI], 1.04-2.06; P=. 02) and age at CD onset (OR, 1.1; 95% CI, 1.01-1.20; P=. 03) predicted LOR. As to IFX and ADA efficacies after 1 year of administration, there were no significant differences in event-free rates for the 5 years after biologic introduction or the secondary LOR rate. CRP at biologic introduction and age at CD onset predicted LOR.
  • Uehara T, Matsumoto S, Miyatani H, Mashima H
    Clinical medicine insights. Gastroenterology 10 1179552217728906  2017年 [査読有り][通常論文]
  • 新しい大腸内視鏡前処置薬は本当に優れているか? 高張PEG液(新P)と等張クエン酸マグネシウム液(M)での大腸内視鏡挿入時間の比較 付.洗浄度と受容性(飲みやすさ)に関してのレビュー
    松本 博成, 石田 茂夫, 宮谷 博幸, 眞嶋 浩聡
    埼玉県医学会雑誌 51 1 326 - 333 埼玉県医学会 2016年11月 [査読無し][通常論文]
     
    2種の大腸内視鏡前処置薬polyethilene glycol(PEG)高張液(新P)と等張クエン酸マグネシウム液(M)の大腸内視鏡挿入時間を比較し、腸管洗浄度および患者受容性について比較検討した。対象は、新P法使用23例(男女比0.48、平均年齢54.7歳)、M法使用22例(男女比0.38、平均年齢57.6歳)である。その結果、新P法はM法と比較して大腸内視鏡平均挿入時間が長い傾向で、洗浄度、受容度ともに劣ることが示唆された。また、M法の方が医療費が安く経済性が高いことが分かった。
  • Watanabe N, Mashima H, Miura K, Goto T, Yoshida M, Goto A, Ohnishi H
    Cellular and molecular gastroenterology and hepatology 2 6 767 - 782 2016年11月 [査読有り][通常論文]
     
    Background & Aims Proliferation, differentiation, and morphogenesis of the intestinal epithelium are tightly regulated by a number of molecular pathways. Coordinated action of intestine is achieved by gastrointestinal hormones, most of which exert these actions through G-protein–coupled receptors. We herein investigated the role of Gαq/11-mediated signaling in intestinal homeostasis. Methods Intestinal tissues from control (Gnaqflox/floxGna11+/+), Int-Gq knock-out (KO) (VilCre+/-Gnaqflox/floxGna11+/+), G11 KO (Gnaqflox/floxGna11-/-), and Int-Gq/G11 double knock-out (DKO) (VilCre+/-Gnaqflox/floxGna11-/-) mice were examined by microscopy, transmission electron microscopy, and immunohistochemistry. The effect of Gαq/11-mediated signaling was studied in the cell lineage, proliferation, and apoptosis. Dextran sodium sulfate (DSS) colitis was induced to study the role of Gαq/11 in colon. Results Paneth cells were enlarged, increased in number, and mislocalized in Int-Gq/G11 DKO small intestine. Paneth cells also reacted with PAS and Muc2 antibody, indicating an intermediate character of Paneth and goblet cells. The nuclear β-catenin, T-cell factor 1, and Sox9 expression were reduced severely in the crypt base of Int-Gq/G11 DKO intestine. Proliferation was activated in the crypt base and apoptosis was enhanced along the crypt. Int-Gq/G11 DKO mice were susceptible to DSS colitis. Proliferation was inhibited in the crypt of unaffected and regenerative areas. Cystic crypts, periodic acid–Schiff–positive cells, and Muc2-positive cells were unusually observed in the ulcerative region. Conclusions The Gαq/11-mediated pathway plays a pivotal role in the preservation of intestinal homeostasis, especially in Paneth cell maturation and positioning. Wnt/β-catenin signaling was reduced significantly in the crypt base in Gαq/G11-deficient mice, resulting in the defective maturation of Paneth cells, induction of differentiation toward goblet cells, and susceptibility to DSS colitis.
  • Kenichi Yamanaka, Hiroyuki Miyatani, Yukio Yoshida, Takehiro Ishii, Shinichi Asabe, Osamu Takada, Mitsuhiro Nokubi, Hirosato Mashima
    BMC GASTROENTEROLOGY 16 1 130  2016年10月 [査読有り][通常論文]
     
    Background: Gastric foveolar hyperplastic polyps (GFHPs) are common findings in clinical practice. GFHPs commonly arise in a background of chronic atrophic gastritis, including autoimmune gastritis (type A gastritis), and have a potential risk of malignant transformation. Case presentation: In 2005, a 55-year-old Japanese woman underwent upper endoscopy at another hospital and was found to have a pedunculated polyp (10 mm in diameter) on the greater curvature of the lower gastric body. On biopsy, the polyp was diagnosed as a GFHP. Nine years later, the polyp had grown to 20 mm in diameter, and the biopsy specimen taken at this time showed tubular adenocarcinoma. On admission to our hospital, the serum Helicobacter Pylori (H. pylori) immunoglobulin G antibody and stool H. pylori antigen were both negative. Anti-gastric parietal cell antibody was positive, as was the anti-intrinsic factor antibody, and the fasting serum gastrin level was markedly increased. In 2014, en bloc resection of the pedunculated polyp was performed by endoscopic submucosal dissection. The final histological diagnosis was adenocarcinoma of the stomach with submucosal and lymphatic invasion. Subsequently, additional radical distal gastrectomy was performed. At the latest follow-up (12 months postoperatively), no recurrence was noted. Conclusions: We here reported a rare case of malignant transformation of GFHP arising in a context of type A gastritis. To our knowledge, there are no previous reports on malignant transformation of GFHP with submucosal and lymphatic invasion arising in a background of type A gastritis in the English literature. Further, there is currently no effective treatment other than endoscopic or surgical treatment for such cases. Given the potential risk of malignant transformation due to hypergastrinemia, we consider that endoscopic treatment should be considered as a first-line therapy when a malignant growth is suspected.
  • 【肝胆膵疾患とオートファジー】 オートファジー異常と肝胆膵疾患 急性膵炎とオートファジー
    眞嶋 浩聡, 大西 洋英
    肝・胆・膵 73 2 243 - 249 (株)アークメディア 2016年08月 [査読無し][通常論文]
  • 石井 剛弘, 宮谷 博幸, 中島 嘉之, 眞嶋 浩聡
    Progress of Digestive Endoscopy 88 1 120,9 - 121,9 (一社)日本消化器内視鏡学会-関東支部 2016年06月 [査読無し][通常論文]
     
    症例は58歳男性で、1週間ほど前に空腹時心窩部痛、嘔気、嘔吐が出現し、近医で胃炎と診断された。H2ブロッカーと胃粘膜保護薬を処方されたが、深夜に症状が増悪し、救急搬送された。血液検査所見で好中球優位の白血球高増加、直接型優位のビリルビン値上昇、肝胆道系酵素上昇を認めた。腹部CT所見では両側の肝内胆管、総胆管が拡張しており、十二指腸乳頭部近傍の下部胆管内に10mm大の高吸収域を認めた。胆石性胆管炎の診断で緊急内視鏡的逆行性胆管膵管造影を施行し、生検で十二指腸乳頭部腺腫と診断した。内視鏡的乳頭切除術(EP)を施行したところ、切除病理組織所見は高度異型を伴う管状絨毛腺腫で断端陰性であった。EP施行後第12病日に残存する総胆管結石に対して内視鏡的切石術を行い、胆管開口部をEPBDバルーンで拡張し採石バルーンで排石した。その後の経過は良好で、半年後の内視鏡MR胆管膵管撮影で乳頭部腺腫や胆管結石の再発を認めていない。
  • Satohiro Matsumoto, Hirosato Mashima
    INTERNATIONAL JOURNAL OF COLORECTAL DISEASE 31 4 921 - 922 2016年04月 [査読有り][通常論文]
  • Shindo Y, Matsumoto S, Miyatani H, Yoshida Y, Mashima H
    World journal of gastrointestinal endoscopy 8 7 349 - 356 2016年04月 [査読有り][通常論文]
  • 眞嶋 浩聡, 大西 洋英
    膵臓 31 1 17 - 24 日本膵臓学会 2016年02月 [査読無し][通常論文]
     
    急性膵炎はトリプシンの異所性活性化が中心的な役割を果たすと考えられてきたが、NF-κBの活性化、オートファジー不全、酸化ストレス、小胞体ストレス、細胞内カルシウムの異常などの多くの異常が同時に進行することが明らかとなってきた。これらにも進行の序列はあるはずだが、未だ明らかにされておらず、急性膵炎の発症のメカニズムの詳細は不明のままである。膵酵素の調節性外分泌は細胞内カルシウムによって制御されている。アセチルコリンやコレシストキニンの分泌刺激が基底膜側の受容体から入ると頂端側にカルシウムスパイクが生じて開口放出が起こる。過剰な分泌刺激などを加えて膵炎を発症させると細胞内全体に異常なカルシウム濃度の上昇がみられて遷延する。その異常な上昇をカルシウム結合蛋白やキレート剤、カルシウムチャンネルの阻害剤などを用いて制御すると膵炎発症が抑制されることが明らかになってきた。本項ではカルシウムシグナルに焦点をあてて膵炎との関係を概説する。(著者抄録)
  • Satohiro Matsumoto, Hirosato Mashima
    Case Reports in Gastroenterology 10 1 157 - 160 2016年 [査読有り][通常論文]
     
    Diversion colitis is a benign inflammatory process that occurs in any part of the large bowel excluded from the fecal stream by a diverting colostomy. While most of the patients with diversion colitis usually are asymptomatic, a minority has abdominal pain and rectal discharge of blood or mucus. A 65-year-old Japanese man was diagnosed as having diversion colitis with ulcerative colitis at 4 months after subtotal colectomy. Corticosteroid and mesalazine enemas were started nonsynchronously. A proctoscopy after 2 months showed no response. Prednisolone injections were started at 1.0 mg/kg daily, but the mucosal inflammation still failed to improve. A combined mesalazine 1 g plus prednisolone sodium phosphate 20 mg enema was started once daily. The rectal bleeding and endoscopic findings improved. Finally proctectomy and ileal pouch-anal anastomosis were successfully performed. A combined mesalazine plus corticosteroid enema may be effective in patients with diversion colitis associated with ulcerative colitis.
  • 【肝・胆・膵の慢性炎症】 膵臓・胆道系と慢性炎症 膵炎の病態
    大西 洋英, 眞嶋 浩聡
    別冊Bio Clinica: 慢性炎症と疾患 4 4 71 - 75 (株)北隆館 2015年12月 [査読無し][通常論文]
     
    膵臓の3大疾患とも言うべき急性膵炎、慢性膵炎、ならびに膵臓癌は依然難治性疾患であり、未だこれら疾患の画期的な予防法および治療法は開発されていない。一方、これら疾患の病態を解明し新たな治療法を開発すべく多くの研究者が膵疾患基礎研究に日夜尽力してきた結果、急性膵炎発症機転や慢性膵炎の発症・進展に関して新たな知見が次々と得られている。急性膵炎におけるオートファジー機構の関与や慢性膵炎の発症・進展における膵星細胞の役割がその代表的なものである。本稿ではこれら膵疾患の病態に関する知見を概説する。(著者抄録)
  • 【膵癌の浸潤・転移に関する基礎研究の最前線-臨床応用に向けて-】 膵癌の発癌、進展におけるインターフェロンシグナル経路の役割
    眞嶋 浩聡, 酒井 利隆, 大西 洋英
    胆と膵 36 10 1147 - 1153 医学図書出版(株) 2015年10月 [査読無し][通常論文]
     
    I型インターフェロンは抗ウイルス作用にとどまらず、免疫調整作用や抗腫瘍効果などの多彩な生物学的活性を有している。インターフェロン制御因子(IRF)はインターフェロン誘導遺伝子の転写を制御する因子として発見されたが、免疫関連遺伝子の転写調節の他に、細胞増殖・アポトーシスの制御、癌化などに関与する。膵臓においてIRF2は調節性外分泌にかかわっており、IRF2ノックアウトマウスの膵臓は急性膵炎の発症初期像を呈する。また、膵癌においてIRF1は癌抑制遺伝子、IRF2は癌遺伝子としての機能を有していることが明らかとなった。生物学的悪性度が高く、浸潤傾向が強い膵癌に対しては、多方面からの治療が不可欠である。インターフェロンシグナルの膵癌の発癌、進展に及ぼす影響やIRFの分子メカニズムの解明を進めることによって、膵癌の新たな治療法に結びつく可能性がある。(著者抄録)
  • 【オートファジーと消化器疾患】 膵炎とオートファジー
    眞嶋 浩聡, 大西 洋英
    G.I.Research 23 3 219 - 226 (株)先端医学社 2015年06月 [査読無し][通常論文]
     
    膵臓は消化・吸収のための消化酵素を高率に産生するがゆえに、小胞体ストレスや酸化ストレスに曝されやすい。急性膵炎の発症にはトリプシンの異所性活性化やNF-κBの活性化、細胞内ストレス、オートファジーなどが関与している。オートファジーは老廃物の分解やリサイクルを通して細胞の恒常性の維持に寄与するが、膵炎発症時にも細胞内環境を維持するために動員されると考えられる。しかし、機能不全に陥って膵炎の発症に関与し、p62/SQSTM1(p62)の蓄積や転写因子Nrf2の活性化が細胞内で生じる。p62はオートファジーの基質であるだけでなく、シグナル伝達、細胞増殖、アポトーシス、炎症などをつなぐハブとしての機能を有している。オートファジーと膵炎発症の関係が注目されており、p62やKeap1-Nrf2を介するシグナルが重要な役割を果たしている可能性がある。(著者抄録)
  • Mitsuaki Ishioka, Mario Jin, Tamotsu Matsuhashi, Suguru Arata, Yusato Suzuki, Noboru Watanabe, Masayuki Sawaguchi, Noriyoshi Kanazawa, Kengo Onochi, Natsumi Hatakeyama, Shigeto Koizumi, Hirosato Mashima, Hirohide Ohnishi
    INTERNAL MEDICINE 54 19 2439 - 2442 2015年 [査読有り][通常論文]
     
    Primary enterolith is a rare condition that can induce ileus and intestinal perforation. We report the first case of a true primary enterolith treated by balloon-assisted enteroscopy. The patient presented with a small intestinal ileus. After its improvement following the insertion of an ileus tube, radiography with amidotrizoate sodium meglumine detected a round, movable defect in the ileum measuring 42 mm diameter. The patient was diagnosed with a primary enterolith based on her past history. The enterolith was fractured and removed using balloon-assisted enteroscopy. This case suggests that balloon-assisted enteroscopy may be an effective non-invasive treatment option for enteroliths.
  • Toshitaka Sakai, Hirosato Mashima, Yumi Yamada, Takashi Goto, Wataru Sato, Takahiro Dohmen, Kentaro Kamada, Masato Yoshioka, Hiroshi Uchinami, Yuzo Yamamoto, Hirohide Ohnishi
    PANCREAS 43 6 909 - 916 2014年08月 [査読有り][通常論文]
     
    Objective: Pancreatic cancer is one of the most malignant diseases worldwide. Interferon regulatory factor (IRF) 1 and IRF2 function as a tumor suppressor and oncoprotein, respectively, in several types of cancers. We investigated whether IRF1 and IRF2 are involved in the progression of pancreatic cancer. Methods: We examined the expressions of IRF1 and IRF2 in pancreatic cancer specimens and analyzed the association with clinicopathologic features. We evaluated the biological effects of IRF1 and IRF2 using a pancreatic cancer cell line. Results: The expression levels of IRF1 and IRF2 were decreased and increased, respectively, in the pancreatic cancer cells compared with those observed in the paired normal areas. A higher expression of IRF1 was associated with better features of tumor differentiation, infiltration depth, tumor size, and survival, whereas that of IRF2 was associated with a worse feature of tumor infiltration depth. Interferon regulatory factor 2-overexpressing PANC-1 cells exhibited an increase in cell growth, less apoptotic features, and chemoresistance to gemcitabine treatment. In contrast, IRF1-overexpressing cells exhibited the opposite characteristics. Conclusions: Interferon regulatory factors 1 and 2 may regulate the progression of pancreatic cancer by functioning as an antioncoprotein and oncoprotein, respectively. These molecules may serve as potential targets of therapy.
  • 【新しい視点にたった膵内外分泌相関】 膵ホルモンおよびActivin Aと膵機能
    大西 洋英, 眞嶋 浩聡
    胆と膵 35 4 317 - 322 医学図書出版(株) 2014年04月 [査読無し][通常論文]
     
    膵臓は外分泌機能を担う膵腺房および導管、内分泌機能を担うランゲルハンス氏島、ならびに膵星細胞などによって構成される臓器である。とくにランゲルハンス氏島(ラ氏島)の各種内分泌細胞にて産生・分泌される膵ホルモンは膵腺房細胞の生理的機能を制御していると考えられている。さらに最近では、生理的条件下ならびに各種病態において膵臓においてTGF-betaスーパーファミリーに属するサイトカインであるactivin Aが発現し、膵の発生、分化、ならびに線維化などにおいて大きな役割を果たしていることが明らかになってきている。本稿では、膵内分泌相関として知られる膵ホルモンの膵外分泌機構への作用とその分子機序、ならびにactivin Aのさまざまな膵生理機能ならびに膵疾患病態に対する作用を中心に紹介する。(著者抄録)
  • Masayuki Sawaguchi, Mario Jin, Tamotsu Matsuhashi, Reina Ohba, Natsumi Hatakeyama, Shigeto Koizumi, Kengo Onochi, Yumi Yamada, Noriyoshi Kanazawa, Yuko Kimura, Shin Tawaraya, Noboru Watanabe, Yusato Suzuki, Hirosato Mashima, Hirohide Ohnishi
    GASTROINTESTINAL ENDOSCOPY 79 4 681 - 685 2014年04月 [査読有り][通常論文]
  • Shin Tawaraya, Mario Jin, Tamotsu Matsuhashi, Yusato Suzuki, Masayuki Sawaguchi, Noboru Watanabe, Kengo Onochi, Shigeto Koizumi, Natsumi Hatakeyama, Reina Ohba, Hirosato Mashima, Hirohide Ohnishi
    GASTROINTESTINAL ENDOSCOPY 79 3 525 - 530 2014年03月 [査読有り][通常論文]
  • Shigeto Koizumi, Mario Jin, Tamotsu Matsuhashi, Shin Tawaraya, Noboru Watanabe, Masayuki Sawaguchi, Noriyoshi Kanazawa, Yumi Yamada, Kengo Onochi, Yuko Kimura, Reina Ohba, Jinko Kataoka, Natsumi Hatakeyma, Hirosato Mashima, Hirohide Ohnishi
    GASTROINTESTINAL ENDOSCOPY 79 2 348 - 353 2014年02月 [査読有り][通常論文]
  • Midori Noma, Masahiro Ohara, Yuki Imaoka, Hirosato Mashima, Shinori Mizota, Sho Okimoto, Yuji Takakura, Koichi Oishi, Toshihiko Kohashi, Satoshi Ikeda, Yasuhiro Fudaba, Yasuhiro Matsugu, Tatsuro Ishimoto, Hideki Nakahara, Takashi Urushihara, Toshiyuki Itamoto, Mihoko Doi, Takashi Nishisaka
    Japanese Journal of Cancer and Chemotherapy 41 4 483 - 486 2014年 [査読有り][通常論文]
     
    We report a case of a 64-year-old woman with Stage IV breast cancer who responded well to chemotherapy containing bevacizumab. She noticed a left breast tumor with acute progression and was diagnosed as having Stage IV, estrogen receptor (ER) (-), progesterone receptor (PgR) (-), human epidermal growth factor receptor 2 (HER2) (-) breast cancer (T4cN3cM1 [lymph nodes]). She received 5 courses of adriamycin (60 mg/m2) plus cyclophosphamide (600mg/m2) (AC therapy) and 4 courses of weekly paclitaxel (PTX 90 mg/m2) plus bevacizumab (AVA 10 mg/m2) as systemic therapy. Computed tomography (CT) and magnetic resonance imaging (MRI) revealed a complete response (CR). After local resection of the breast tumor and radiation to the breast and regional lymph nodes, capecitabine therapy was initiated. Currently, at 5 months after surgery, no new lesion has been detected.
  • Ken Watanabe, Noboru Watanabe, Mario Jin, Tamotsu Matsuhashi, Shigeto Koizumi, Kengo Onochi, Masayuki Sawaguchi, Shin Tawaraya, Hideaki Miyazawa, Hiroshi Uchinami, Yuzo Yamamoto, Hiroshi Nanjo, Hirohide Ohnishi, Hirosato Mashima
    Clinical Journal of Gastroenterology 7 1 41 - 47 2014年 [査読有り][通常論文]
     
    We describe the case of a 74-year-old female with a mesenteric lymph node abscess caused by a Yersinia enterocolitica infection. She had been administered an immunosuppressive drug and was admitted to the hospital due to a high fever, right lower abdominal pain and advanced leukocytosis. We initially diagnosed her with lymphadenitis based on the symptoms and the imaging studies. However, conservative treatment with antibiotics did not yield any improvement, and abscess formation was suspected. Surgical treatment was performed, and the culture from the drainage fluid grew Y. enterocolitica. The histological findings suggested that an ulcerative lesion of the terminal ileum was the entry port of Y. enterocolitica. The pathogen infected the mesenteric lymph nodes and spread along the ileocecal lymphatic vessels, resulting in the formation of an abscess. We also provide a review of the previously published literature on lymph node abscesses due to Y. enterocolitica infections. © Springer 2014.
  • Hirosato Mashima, Hirohide Ohnishi
    Journal of Japanese Society of Gastroenterology 111 8 1550 - 1560 2014年 [査読有り][通常論文]
  • What's New in SURGERY FRONTIER(第78回) 臓器星細胞の機能 膵線維化と膵星細胞
    眞嶋 浩聡, 大西 洋英
    Surgery Frontier 20 3 320 - 323 (株)メディカルレビュー社 2013年09月 [査読無し][通常論文]
  • 膵臓がんにおけるIRF1およびIRF2の役割
    酒井 利隆, 眞嶋 浩聡, 大西 洋英
    膵臓 28 3 422 - 422 日本膵臓学会 2013年06月 [査読無し][通常論文]
  • Yamada Y, Mashima H, Sakai T, Matsuhashi T, Jin M, Ohnishi H
    Digestive diseases and sciences 58 5 1207 - 1217 2013年05月 [査読有り][通常論文]
     
    Background and Aims: Transforming growth factor-β1 (TGF-β1) is one of the growth factors expressed in the gut, and has been shown to play an important role in intestinal mucosal healing. We investigated the effects of TGF-β1 on the cellular functions of intestinal epithelial cells, and also evaluated its signaling pathways in these cells. Methods: We used the rat IEC-6 intestinal epithelial cell line for these studies. The expression of TGF-β1/Smad signaling molecules was examined. We evaluated the effect of TGF-β1 on the proliferation and differentiation by the BrdU incorporation assay and real-time PCR. We manipulated the expression levels of Smad2 and Smad3 using an adenovirus system and small interfering RNA to examine the signaling pathways. The expression of Smad2 and Smad3 along the crypt-villus axis was also examined in the murine intestine. Results: IEC-6 cells produced TGF-β1 and expressed functional TGF-β/Smad signaling molecules. The addition of TGF-β1 in the culture medium suppressed the proliferation and increased the expression of a differentiation marker of enterocytes, in a dose-dependent manner. The adenovirus-mediated and small interfering RNA-mediated studies clearly showed that the growth inhibitory effect and the promotion of differentiation were exerted through a Smad3-dependent and a Smad2-dependent pathway, respectively. IEC-6 cells exhibited upregulated expression of an inhibitory Smad (Smad7) as a form of negative feedback via a non-Smad pathway. Smad2 was predominantly expressed in villi, and Smad3 in crypts. Conclusions: TGF-β1 regulates the cellular functions of intestinal epithelial cells through both Smad-dependent and non-Smad pathways. © 2013 Springer Science+Business Media New York.
  • Hirosato Mashima, Hideki Ohno, Yumi Yamada, Toshitaka Sakai, Hirohide Ohnishi
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 432 4 586 - 592 2013年03月 [査読有り][通常論文]
     
    Insulin-like peptide 5 (INSL5) is a member of the insulin superfamily, and is a potent agonist for RXFP4. We have shown that INSL5 is expressed in enteroendocrine cells (EECs) along the colorectum with a gradient increase toward the rectum. RXFP4 is ubiquitously expressed along the digestive tract. INSL5-positive EECs have little immunoreactivity to chromogranin A (CgA) and might be a unique marker of colorectal EECs. CgA-positive EECs were distributed normally along the colorectum in INSL5 null mice, suggesting that INSL5 is not required for the development of CgA-positive EECs. Exogenous INSL5 did not affect the proliferation of human colon cancer cell lines, and chemically-induced colitis in INSL5 null mice did not show any significant changes in inflammation or mucosa] healing compared to wild-type mice. In contrast, all of the rectal neuroendocrine tumors examined co-expressed INSL5 and RXFP4. INSL5 may be a unique marker of colorectal EECs, and INSL5 RXFP4 signaling might play a role in an autocrine/ paracrine fashion in the colorectal epithelium and rectal neuroendocrine tumors. (C) 2013 Elsevier Inc. All rights reserved.
  • Masayuki Sawaguchi, Mario Jin, Tamotsu Matsuhashi, Reina Ohba, Natsumi Hatakeyama, Shigeto Koizumi, Kengo Onochi, Shin Tawaraya, Noboru Watanabe, Hiroshi Uchinami, Yuzo Yamamoto, Hirohide Ohnishi, Hirosato Mashima
    INTERNAL MEDICINE 52 14 1579 - 1583 2013年 [査読有り][通常論文]
     
    We herein describe the case of a 51-year-old man with a duodenocolic fistula (DCF) caused by a stomal ulcer. The patient complained of watery diarrhea, dysgeusia and malnutrition. His medical history included distal gastrectomy with Billroth I reconstruction for duodenal ulcer perforation. A combination study using endoscopy and contrast imaging confirmed the presence of DCF. Laparotomic fistulectomy was performed, which resulted in the patient's recovery from diarrhea and malnutrition. The histological findings suggested that the fistula had originated from a stomal ulcer. In patients with chronic watery diarrhea of obscure origin following gastrectomy, DCF is a possible cause of the diarrhea.
  • Mashima H
    Nihon Naika Gakkai zasshi. The Journal of the Japanese Society of Internal Medicine 100 11 3215 - 3223 2011年11月 [査読有り][通常論文]
  • 後藤田 卓志, 石川 秀樹, 草野 央, 横井 千寿, 池原 久朝, 櫻井 俊之, 渡辺 一弘, 忌部 航, 向井 俊太郎, 河野 真, 岸田 圭弘, 安保 まり子, 土田 里子, 小泉 重仁, 小野地 研吾, 鎌田 健太郎, 金沢 憲由, 眞嶋 浩聡, 大西 洋英
    Helicobacter Research 15 5 439 - 446 (株)先端医学社 2011年10月 [査読無し][通常論文]
     
    胃がん検診は、X線検査のみがいくつかの症例対照研究によって死亡率減少効果を示したことにより対策型検診として推奨されている。一方で近年、血清検査を用いた効率的な胃がん検診法が提唱されている。しかし、内視鏡検診も含めて有効性の評価がなされていないのが現状である。そこで、新しい胃がん検診システムの評価をおこなうことを目的として、「X線検査・精査内視鏡検査群」(バリウム検診群)と「抗H.pylori抗体+ペプシノゲン測定・内視鏡検査群」(血清胃癌リスク検診群)の無作為化比較対照試験をスタートさせた。(著者抄録)
  • Hirosato Mashima, Taku Sato, Yasuo Horie, Yuko Nakagawa, Itaru Kojima, Toshiaki Ohteki, Hirohide Ohnishi
    GASTROENTEROLOGY 141 3 1102 - U459 2011年09月 [査読有り][通常論文]
     
    BACKGROUND & AIMS: Pancreatic acinar cells are used to study regulated exocytosis. We investigated the role of interferon regulatory factor-2 (IRF2) in exocytosis in pancreatic acinar cells. METHODS: Pancreas tissues from Irf2(+/+), Irf2(+/-) and Irf2(-/-) mice were examined by microscopy, immunohistochemical, and immunoblot analyses; amylase secretion was quantified. We also compared salivary glands and pancreatic islets of Irf2(-/-) mice with those of Irf2(+/-) mice. To examine the effects of increased signaling by type I interferons, we studied pancreatic acini from Irf2(-/-) Ifnar1(-/-) mice. The effect of IRF2 on amylase secretion was studied using an acinar cell line and a retroviral system. We studied expression of IRF2 in wild-type mice with cerulein-induced pancreatitis and changes in pancreatic tissue of Irf2(-/-) mice, compared with those of Irf2(+/-) mice. RESULTS: Irf2(-/-) pancreas was white and opaque; numerous and wide-spread zymogen granules were observed throughout the cytoplasm, along with lack of fusion between zymogen granules and the apical membrane, lack of secretagogue-stimulated amylase secretion, and low serum levels of amylase and elastase- 1, indicating altered regulation of exocytosis. The expression pattern of soluble N-ethylmaleimide-sensitive factor attachment protein receptors changed significantly, specifically in pancreatic acini, and was not rescued by disruption of type I interferon signaling. Down-regulation of IRF2 decreased amylase secretion in an acinar cell line. In mice with pancreatitis, levels of IRF2 were reduced. Irf2(-/-) acini were partially resistant to induction of pancreatitis. CONCLUSIONS: IRF2 regulates exocytosis in pancreatic acinar cells; defects in this process might be involved in the early phases of acute pancreatitis.
  • Satoshi Shinozaki, Hirosato Mashima, Hirohide Ohnishi, Kentaro Sugano
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 393 1 61 - 65 2010年02月 [査読有り][通常論文]
     
    In chronic pancreatitis, pancreatic stellate cells (PSCs) play a central role in tissue fibrogenesis. Transforming growth factor beta(1) (TGF-beta(1)) and the Th2 lymphokines such as interleukin (IL)-13 are major profibrogenic cytokines in many organs. Activated PSCs produce various inflammatory cytokines including TGF-beta(1). In this study, we investigated whether IL-13 affects pancreatic fibrogenesis by modulating the functions of PSCs. IL-13 promoted PSCs proliferation without activation through the suppression of autocrine TGF-beta(1). IL-13 enhanced Stat6 phosphorylation in PSCs but Stat6 was not involved in the suppression of TGF-beta(1). IL-13 inhibited the transcriptional activity of NF-kappa B, and the expression of mutant I-kappa B reproduced the suppression of autocrine TGF-beta(1) and promoted PSCs proliferation. Taken together, we demonstrated that IL-13 promotes PSCs proliferation through the suppression of the transcriptional activity of NF-kappa B, resulting in the decrease of autocrine TGF-beta(1). This finding provides an unequivocal evidence of IL-13 participation in pancreatic fibrosis, illustrating a new strategy for chronic pancreatitis. (C) 2010 Elsevier Inc. All rights reserved.
  • Naoko Watanabe, Hitoshi Ikeda, Yukio Kume, Yumiko Satoh, Makoto Kaneko, Daiya Takai, Kazuaki Tejima, Masakazu Nagamine, Hirosato Mashima, Tomoaki Tomiya, Eisei Noiri, Masao Omata, Masanori Matsumoto, Yoshihiro Fujimura, Yutaka Yatomi
    THROMBOSIS AND HAEMOSTASIS 102 2 389 - 396 2009年08月 [査読有り][通常論文]
     
    Although hepatic stellate cells, endothelial cells, glomerular podocytes and plateles were reported to be a source of ADAMTS13, it is not clarified which source is involved in the regulation of plasma ADAMTS13 activity. It was demonstrated previously that selective hepatic stellate cell damage in rats caused decreased plasma ADAMTS13 activity. To further elucidate the potential contribution of hepatic stellate cells to the regulation of plasma ADAMTS13 activity, this study examined plasma ADAMTS13 activity when hepatic stellate cells proliferate during the process of liver fibrosis by employing rat models of liver fibrosis due to cholestasis, bile duct ligation, and steatohepatitis, a choline-deficient L-amino acid-defined-diet. ADAMTS13 expression was increased with co-localisation with smooth muscle alpha-actin, a marker of hepatic stellate cells, in bile duct-ligated livers up to four weeks, in which a close correlation between ADAMTS13 and smooth muscle alpha-actin mRNA expressions was determined. Plasma ADAMTS13 activity, measured by a sandwich ELISA involving a specific substrate to ADAMTS I 3,was increased in bile duct-ligated rats with a significant correlation with ADAMTS13 mRNA expression levels in the liver. Furthermore, ADAMTS13 mRNA expression was increased with enhanced mRNA expression in smooth muscle alpha-actin in the livers of rats fed a choline-deficient L-amino acid-defined-diet for 16 weeks, in which increased plasma ADAMTS13 activity was determined. Thus, increased plasma ADAMTS13 activity in cholestasis and steatohepatitis in rats may be due, at least in part,to enhanced ADAMTS13 production in the liver, suggesting a significant role of hepatic stellate cells in the regulation of plasma ADAMTS13 activity.
  • Yukako Yoshikumi, Hideki Ohno, Junko Suzuki, Masashi Isshiki, Yasuyuki Morishita, Hirohide Ohnishi, Hiroshi Yasuda, Masao Omata, Toshiro Fujita, Hirosato Mashima
    ENDOCRINE JOURNAL 55 4 757 - 765 2008年08月 [査読有り][通常論文]
     
    Pancreatic AR42J cells demonstrate the pluripotency in precursor cells of the gut endoderm and also provide an excellent model system to study the differentiation of the pancreas. Using the mRNA differential display technique, we identified junctional adhesion molecule-1 (JAM-1), a component of the tight junction, was highly up-regulated during the differentiation of AR42J cells, although junctions were not formed. The expression level of JAM-1 showed an up-regulation in the mRNA level after 3 hours and in the protein level after 24 hours in [activin A + betacellulin]-treated AR42J cells. The expressions of its signaling molecules, PAR-3 and atypical PKC lambda, also increased after the addition of activin A + betacellulin. When JAM-1 was over-expressed in [activin A + betacellulin]-treated AR42J cells, tagged-JAM-1 was observed in cytoplasm as vesicular structures and JAM-1 was colocalized with Rab3B and Rab13, members of the Rab family expressed at tight junctions. In streptozotocin-induced regenerating islets, the expression of JAM-1 was also up-regulated in the mRNA level and the protein level. JAM-1 might therefore play an important role in the differentiation of AR42J cells and the regeneration of pancreatic islets.
  • Satoshi Shinozaki, Hirohide Ohnishi, Kouji Hama, Hiroto Kita, Hironori Yamamoto, Hiroyuki Osawa, Kiichi Satu, Kiichi Tamada, Hirosato Mashima, Kentaro Sugano
    JOURNAL OF CELLULAR PHYSIOLOGY 216 1 38 - 46 2008年07月 [査読有り][通常論文]
     
    Indian hedgehog (Ihh) is a member of hedgehog peptides family that exerts diverse effects on multiple cellular functions. Since Ihh expression is elevated in the pancreas of chronic pancreatitis patients, Ihh has been assumed to participate in the chronic pancreatic injury, especially in pancreatic fibrosis. However, its function in pancreatic fibrosis is still unknown. We thus examined Ihh effects on rat activated pancreatic stellate cells (PSCs) that play a central role in pancreatic fibrosis. Activated PSCs express both patched-I and smoothened that are essential components of hedgehog receptor system. Ihh did not alter the PSC expression of collagen-I or alpha-smooth muscle actin, a parameter of PSC transformation, or did not change PSC proliferation. However, Ihh enhanced PSC migration in both chemotactic and chemokinetic manners. Furthermore, Inn increased the amount of membrane-type I matrix metalloproteinase (MTI-MMP) and altered its localization on the plasma membrane, which plays a stimulatory role in cellular migration. In addition, tissue inhibitor of metalloproteinase-2 (TIMP-2) attenuated lhh-stimulated PSC migration. Since most hedgehog intracellular signals are mediated by Gli-I transcription factor, we investigated its contribution to lhh-enhancement of PSC migration. Ihh induced Gli-I nuclear accumulation in PSCs, indicating that Ihh stimulates Gli-I-dependent signaling pathway in PSCs. Unexpectedly, however, adenovirus-mediated Gli-I overexpression blocked the Inn enhancement of both MTI-MMP localization on the plasma membrane and PSC migration. Furthermore, reduction of Gli-I expression with RNA interference augmented lhh-stimulated PSC migration. These data indicate that lhh promotes PSC migration by enhancing MTI-MMP localization on the plasma membrane but is negatively regulated by Gli-I.
  • Hirosato Mashima, Junko Suzuki, Toshiya Hirayama, Yukako Yoshikumi, Hideki Ohno, Hirohide Ohnishi, Hiroshi Yasuda, Toshiro Fujita, Masao Omata
    INFECTION AND IMMUNITY 76 6 2296 - 2303 2008年06月 [査読有り][通常論文]
     
    Helicobacter pylori-produced cytotoxin VacA induces intracellular vacuolation. The VacA-induced vacuole is assumed to represent the pathological status of intracellular trafficking. The fusion mechanism of the endosomes requires the formation of a tight complex between the Q-SNAREs and the R-SNAREs. We recently reported that syntaxin 7, a family member of the Q-SNARE protein, is involved in VacA-induced vacuole formation. In order to further elucidate the molecular mechanism, we identified the participation of vesicle-associated membrane protein 7 (VAMP7) as a partner of syntaxin 7. Immunocytochemistry revealed endogenous VAMP7 to be localized to the vacuoles induced by VacA. A Northern blotting study demonstrated that VacA intoxication increased VAMP7 mRNA in a time-dependent manner. VAMP7 was coimmunoprecipitated with syntaxin 7, and the amounts of endogenous VAMP7 and syntaxin 7 bound to syntaxin 7 and VAMP7, respectively, increased in response to VacA. The down-regulation of VAMP7 using small interfering RNA inhibited VacA-induced vacuolation, and the transient transfection of dominant-negative mutant VAMP7, the N-terminal domain of VAMP7, also inhibited the vacuolation. We therefore conclude that R-SNARE VAMP7 plays an important role in VacA-induced vacuolation as a partner of Q-SNARE syntaxin 7.
  • Hiroshi Yasuda, Shuko Hirata, Kazuaki Inoue, Hirosato Mashima, Hirohide Ohnishi, Makoto Yoshiba
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 354 1 154 - 159 2007年03月 [査読有り][通常論文]
     
    Bile acids, which have been implicated in gastrointestinal-tract cell carcinogenesis, share properties with tumor promoters in that both affect signal transduction pathways responsible for cell proliferation and apoptosis. In the present study, we demonstrate that EGFR-ERK1/2 is activated following treatment of AGS human gastric carcinoma cells with bile acids. EGFR phosphoactivation is ligand-dependent, since treatment of cells with HB-EGF antisera or CM 197 (a selective inhibitor of HB-EGF) markedly inhibits deoxycholate (DC)-promoted activation. Membrane-type bile acid receptor (M-BAR)/TGR5 is a recently identified G-protein-coupled receptor (GPCR). In AGS cells, siRNAs that target M-BAR suppress DC-induced phosphorylation of EGFR. Furthermore, introduction of siRNAs targeting ADAM17 transcripts resulted in suppression of DC-induced activation of EGFR and ERK1/2. These results suggest that in AGS cells, DC transactivates EGFR through M-BAR- and ADAM/HB-EGF-dependent mechanisms. (c) 2006 Elsevier Inc. All rights reserved.
  • H Osawa, H Ohnishi, K Takano, T Noguti, H Mashima, H Hoshino, H Kita, K Sato, H Matsui, K Sugano
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 344 2 680 - 687 2006年06月 [査読有り][通常論文]
     
    Sonic Hedgehog (Shh), a member of hedgehog peptides family, is expressed in gastric gland epithelium. To elucidate Shh function to gastric mucosal cells, we examined the effect of Shh on the proliferation of a rat normal gastric mucosal cell line, RGM-1. RGM-1 cells express essential components of Shh receptor system, patched-1, and smoothened. Shh enhanced DNA synthesis in RGM-1 cells and elevated intracellular calcium concentration ([Ca2+](i)). In addition, Shh as well as calcium ionophore A32187 rapidly activated ERK. However, Shh failed to activate ERK under calcium-free culture condition. Pretreatment of cells with PD98059 attenuated the DNA synthesis promoted by Shh. Moreover, when cells were pretreated with cyclopamine, Shh could not elevate [Ca2+],, activate ERK or promote DNA synthesis. On the other hand, although Shh induced Gli-1 nuclear accumulation in RGM-1 cells, Shh activated ERK even in cells pretreated with actinomycin D. These results indicate that Shh promotes the proliferation of RGM-1 cells through an intracellular calcium- and ERK-dependent but transcription-independent pathway via Patched/Smoothened receptor system. (c) 2006 Elsevier Inc. All rights reserved.
  • Y Yoshikumi, H Mashima, J Suzuki, Y Yamaji, M Okamoto, K Ogura, T Kawabe, M Omata
    CANADIAN JOURNAL OF GASTROENTEROLOGY 20 4 287 - 290 2006年04月 [査読有り][通常論文]
     
    Dieulafoy's ulcer is a rare cause of gastrointestinal bleeding. The lesion is usually located in the stomach, although it may occur anywhere in the gastrointestinal tract. A 44-year-old man was admitted to hospital due to cerebral infarction. On the 23rd day of hospitalization, he showed massive hematochezia. He underwent an urgent colonoscopy. There was a visible protuberant vessel without significant ulceration at the fundus of the rectum, consistent with a Dieulafoy's ulcer. It was treated by endoscopic hemoclipping. However, rebleeding occurred three times despite repeated hemoclipping. Finally, endoscopic hand ligation was successfully perk formed to achieve permanent hemostasis. Endoscopic hand ligation is an effective treatment for bleeding rectal Dieulafoy's ulcer.
  • H Aoki, H Ohnishi, K Hama, T Ishijima, Y Satoh, K Hanatsuka, A Ohashi, S Wada, T Miyata, H Kita, H Yamamoto, H Osawa, K Sato, K Tamada, H Yasuda, H Mashima, K Sugano
    AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY 290 4 C1100 - C1108 2006年04月 [査読有り][通常論文]
     
    Pancreatic stellate cells ( PSCs) are activated during pancreatitis and promote pancreatic fibrosis by producing and secreting ECMs such as collagen and fibronectin. IL-1 beta has been assumed to participate in pancreatic fibrosis by activating PSCs. Activated PSCs secrete various cytokines that regulate PSC function. In this study, we have examined IL-1 beta secretion from culture-activated PSCs as well as its regulatory mechanism. RT-PCR and ELISA have demonstrated that PSCs express IL-1 beta mRNA and secrete IL-1 beta peptide. Inhibition of TGF-beta(1) activity secreted from PSCs by TGF-beta(1)-neutralizing antibody attenuated IL-1 beta secretion from PSCs. Exogenous TGF-beta(1) increased IL-1 beta expression and secretion by PSCs in a dose-dependent manner. Adenovirus-mediated expression of dominant-negative ( dn) Smad2/3 expression reduced both basal and TGF-beta(1)-stimulated IL-1 beta expression and secretion by PSCs. Coexpression of Smad3 with dnSmad2/3 restored IL-1 beta expression and secretion by PSCs, which were attenuated by dnSmad2/3 expression. In contrast, coexpression of Smad2 with dnSmad2/3 did not alter them. Furthermore, inhibition of IL-1 beta activity secreted from PSCs by IL-1 beta-neutralizing antibody attenuated TGF-beta(1) secretion from PSCs. Exogenous IL-1 beta enhanced TGF-beta(1) expression and secretion by PSCs. IL-1 beta activated ERK, and PD-98059, a MEK1 inhibitor, blocked IL-1 beta enhancement of TGF-beta(1) expression and secretion by PSCs. We propose that an autocrine loop exists between TGF-beta(1) and IL-1 beta in activated PSCs through Smad3- and ERK-dependent pathways.
  • K Hama, H Ohnishi, H Aoki, H Kita, H Yamamoto, H Osawa, K Sato, K Tamada, H Mashima, H Yasuda, K Sugano
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 340 3 742 - 750 2006年02月 [査読有り][通常論文]
     
    Activated pancreatic stellate cells (PSCs) play major roles in promoting pancreatic fibrosis. We previously reported that angiotensin II (Ang II) enhances activated PSC proliferation through EGF receptor transactivation. In the present study, we elucidated a novel intracellular mechanism by which Ang II stimulates cellular proliferation. TGF-beta(1) inhibits activated PSC proliferation via a Smad3 and Smad4-dependent pathway in an autocrine manner. We demonstrated that Ang II inhibited TGF-beta(1)-induced nuclear accumulation of Smad3 and Smad4. Furthermore, Ang II rapidly induced inhibitory Smad7 mRNA expression. Adenovirus-mediated Smad7 overexpression inhibited TGF-beta(1)-induced nuclear accumulation of Smad3 and Smad4, and potentiated activated PSC proliferation. PKC inhibitor Go6983 blocked the induction of Smad7 mRNA expression by Ang II. In addition, 12-O-tetradecanoyl-phorbol 13-acetate, a PKC activator, increased Smad7 mRNA expression. These results Suggest that Ang II enhances activated PSC proliferation by blocking autocrine TGF-beta(1)-mediated growth inhibition by inducing Smad7 expression via a PKC-dependent pathway. (c) 2005 Elsevier Inc. All rights reserved.
  • Y Yoshikumi, H Mashima, N Ueda, K Ohno, J Suzuki, S Tanaka, M Hayashi, N Sekine, H Ohnishi, H Yasuda, T Iiri, M Omata, T Fujita, Kojima, I
    JOURNAL OF CELLULAR BIOCHEMISTRY 95 6 1157 - 1168 2005年08月 [査読有り][通常論文]
     
    Pancreatic AR42J cells have the feature of pluripotency of the precursor cells of the gut endoderm. Betacellulin (BTC) and activin A (Act) convert them into insulin-secreting cells. Using mRNA differential display techniques, we have identified a novel mitochondrial transporter, which is highly expressed during the course of differentiation, and have designated it citrate transporter protein-like protein (CTPL). Recently sideroflexin 1 (Sfxn1) was shown to be a susceptible gene of flexed-tail (f/f) mice, and CTPL has turned out to be, a rat orthologous protein of Sfxn3, a member of sideroflexin family. CTPL/Sfxn3 was targeted to mitochondrial membrane like Sfxn1; The expression levels of CTPL/Sfxn3, Sfxn2, and Sfxn5 were upregulated in the early phase of differentiation into insulin-secreting cells but the expression levels of Sfxn1 and Sfxn3 did not change. All Sfxn family members were expressed in rat pancreatic islet. The expression levels of CTPL/Sfxn3, Sfxn2, and Sfxn5 were also upregulated in islets of streptozotocin-induced diabetic rats. The downregulation of CTPL/Sfxn3 in a rat insulinoma cell line, INS-1, With the antisense oligonucleotide did not affect the insulin secretion. Taken together, CTPL/Sfxn3 and some other family members might be important in the differentiation of pancreatic beta-cells as a channel or a carrier molecule and be related to the regeneration of pancreatic endocrine cells.
  • H Grasberger, HG Ye, H Mashima, GI Bell
    GENE 344 143 - 159 2005年01月 [査読有り][通常論文]
     
    The WD40 repeats containing zinc finger protein 106 (ZFP106) is a conserved mammalian protein of unknown function. However, its cDNA shares an extended region of identity with the scr homology domain 3 binding protein 3 (Sh3bp3) cDNA encoding a protein implicated in the insulin signaling pathway. Asking, whether Zfp106 and Sh3bp3 are products of the same gene, we characterized the structures and transcriptional regulation of Zfp106 and its human homologue, ZFP106. A TATA-less, CpG island associated promoter (PI), was mapped by 5'-RACE to a region 19 kb upstream of the ZFP106 translation start site. P1 is active throughout development and at low levels in all adult tissues examined. A conserved cis-element in the proximal PI region showed specific binding to nuclear respiratory factor-1 (NRF-1). Mutagenesis of this site and transfection of a dominant-negative NRF-1 both revealed the crucial role of NRF-1 in activation of P1. The broad tissue expression of PI was in contrast to the high level of ZFP106 mRNA observed in striated muscle. This prompted additional Y-RACE experiments that established a second, TATA box-containing promoter (P2) upstream of the third coding exon. P1 and P2 transcripts encode proteins with distinct N-terminal sequences, with Sh3hp3 corresponding to a rare, alternatively spliced P2 transcript. P2 initiated transcripts are specifically expressed in striated muscle and their level is strongly upregulated during myogenic, but not adipogenic differentiation. By deletion analysis, the region between nucleotides -296 to +96 was sufficient for robust P2 responsiveness to myogenic differentiation. This response is mediated by the additive effect of binding of myogenin to three critical E boxes within this region. In addition, transcriptional enhancer factor-1 family factors contribute to both basal and myogenesis induced P2 activity. In situ hybridization of mouse embryos confirmed predominant expression of Zfp106 in tissues with high developmental expression of either NRF-1 (brown fat and developing brain) or myogenin (striated muscle). Our results suggest distinct roles of tissue-specific ZFP106 isoforms in growth related metabolism and provide the foundation for further studies into the regulation and function of ZFP106. (C) 2004 Elsevier B.V. All rights reserved.
  • T Miyata, H Ohnishi, J Suzuki, Y Yoshikumi, H Ohno, H Mashima, H Yasuda, T Ishijima, H Osawa, K Satoh, K Sunada, H Kita, H Yamamoto, K Sugano
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 323 1 118 - 124 2004年10月 [査読有り][通常論文]
     
    Membrane-type I matrix metalloproteinase (MT1-MMP) localized on the plasma membrane plays a central role in various normal biological responses including tissue remodeling, wound heeling, and angiogenesis and in cancer cell invasion and metastasis, by functioning as a collagenase and activating other matrix metalloproteinases. In order to elucidate the molecular mechanism of the MT1-MMP targeted localization on the plasma membrane, we examined the participation of syntaxin proteins in MT1-MMP intracellular transport to the plasma membrane in human gastric epithelial AGS cells. Western blotting showed that syntaxin 3 and 4 proteins, which are known to function in intracellular transport towards the plasma membrane, were expressed in AGS cells. Immunocytochemistry revealed that transient transfection of AGS cells with dominant-negative mutant syntaxin 4 decreased plasma membrane MT1-MMP expression. In contrast, transient transfection with either dominant-negative mutant syntaxin 3 or 7 did not affect MT1-MMP localization on the plasma membrane. Cell surface biotinylation assay and Matrigel chamber assay demonstrated that stable transfection with dominant-negative mutant syntaxin 4 decreased the amount of MT1-MMP on the plasma membranes and inhibited the cell invasiveness. We suggest that syntaxin 4 is involved in the intracellular transport of MT1-MMP toward the plasma membrane. (C) 2004 Elsevier Inc. All rights reserved.
  • H Ohnishi, T Miyata, H Yasuda, Y Satoh, K Hanatsuka, H Kita, A Ohashi, K Tamada, N Makita, T Iiri, N Ueda, H Mashima, K Sugano
    JOURNAL OF BIOLOGICAL CHEMISTRY 279 10 8873 - 8878 2004年03月 [査読有り][通常論文]
     
    Pancreatic stellate cells (PSCs) play a major role in promoting pancreatic fibrosis. Transforming growth factor-beta(1) (TGF-beta(1)) regulates PSC activation and proliferation in an autocrine manner. The intracellular signaling pathways of the regulation were examined in this study. Immunoprecipitation and immunocytochemistry revealed that Smad2, Smad3, and Smad4 were functionally expressed in PSCs. Adenovirus-mediated expression of Smad2, Smad3, or dominant-negative Smad2/3 did not alter TGF-beta(1) mRNA expression level or the amount of autocrine TGF-beta(1) peptide. However, expression of dominant-negative Smad2/3 inhibited PSC activation and enhanced their proliferation. Co-expression of Smad2 with dominant-negative Smad2/3 restored PSC activation inhibited by dominant-negative Smad2/3 expression without changing their proliferation. By contrast, co-expression of Smad3 with dominant- negative Smad2/3 attenuated PSC proliferation enhanced by dominant- negative Smad2/3 expression without altering their activation. Exogenous TGF-beta(1) increased TGFbeta(1) mRNA expression in PSCs. However, PD98059, a specific inhibitor of mitogen-activated protein kinase kinase (MEK1), inhibited ERK activation by TGF-beta(1), and consequently attenuated TGF-beta(1) enhancement of its own mRNA expression in PSCs. We propose that TGF-beta(1) differentially regulates PSC activation, proliferation, and TGF-beta(1) mRNA expression through Smad2-, Smad3-, and ERK-dependent pathways, respectively.
  • K Hama, H Ohnishi, H Yasuda, N Ueda, H Mashima, Y Satoh, K Hanatsuka, H Kita, A Ohashi, K Tamada, K Sugano
    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS 315 4 905 - 911 2004年03月 [査読有り][通常論文]
     
    Although angiotensin II (Ang II) is known to participate in pancreatic fibrosis, little is known as to the mechanism by which Ang II promotes pancreatic fibrosis. To elucidate the mechanism, we examined the action of Ang II on the proliferation of rat pancreatic stellate cells (PSCs) that play central roles in pancreatic fibrosis. Immunocytochemistry and Western blotting demonstrated that both Ang II type 1 and type 2 receptors were expressed in PSCs. [H-3]Thymidine incorporation assay revealed that Ang II enhanced DNA synthesis in PSCs, which was blocked by Ang II type 1 receptor antagonist losartan. Western blotting using anti-phospho-epidermal growth factor (EGF) receptor and anti-phospho-extracellular signal regulated kinase (ERK) antibodies showed that Ang II-activated EGF receptor and ERK. Both EGF receptor kinase inhibitor AG1478 and MEK1 inhibitor PD98059 attenuated ERK activation and DNA synthesis enhanced by Ang II. These results indicate that Ang II stimulates PSC proliferation through EGF receptor transactivation-ERK activation pathway. (C) 2004 Elsevier Inc. All rights reserved.
  • H Ohno, S Hirabayashi, A Kansaku, Yao, I, M Tajima, W Nishimura, H Ohnishi, H Mashima, T Fujita, M Omata, Y Hata
    ONCOGENE 22 52 8422 - 8431 2003年11月 [査読有り][通常論文]
     
    MAGI-1 and CASK are membrane-associated guanylate kinases of epithelial junctions. MAGI-1 is localized at tight junctions in polarized epithelial cells, whereas CASK is localized along the lateral membranes. We obtained the KIAA0769 gene product through the yeast two-hybrid screening using MAGI-1 as a bait and named it Carom. Carom has a coiled-coil domain in the middle region, and two src homology 3 domains and a PSD-95/Dlg-A/ZO-1 (PDZ)-binding motif in the C-terminal region. Carom binds to the fifth PDZ domain of MAGI-1 and the calmodulin kinase domain of CASK in vitro. MAGI-1 and CASK bind to the distinct sequences in the C-terminal region of Carom, but still compete with each other for Carom binding. The study using a stable transformant of Madine Darby canine kidney (MDCK) cells expressing GFP-Carom revealed that Carom was partially overlapped by MAGI-1 in MDCK cells, which have not yet established mature cell junctions, but became separated from MAGI-1 and colocalized with CASK in polarized cells. Carom was highly resistant to Triton X-100 extractions and recruited CASK to the Triton X-100-insoluble structures. Carom is a binding partner of CASK, which interacts with CASK in polarized epithelial cells and may link it to the cytoskeleton.
  • J Suzuki, H Ohnishi, A Wada, T Hirayama, H Ohno, N Ueda, H Yasuda, T Iiri, Y Wada, M Futai, H Mashima
    JOURNAL OF BIOLOGICAL CHEMISTRY 278 28 25585 - 25590 2003年07月 [査読有り][通常論文]
     
    The Helicobacter pylori-produced cytotoxin VacA induces intracellular vacuolation. The formed vacuole is assumed to be a hybrid of late endosome and lysosome. To elucidate the molecular mechanism of VacA-induced vacuolation, we examined the participation of syntaxin 7 in the human gastric epithelial cell line AGS. Immunocytochemistry revealed that endogenous syntaxin 7 was localized to vacuoles induced by VacA. Northern and Western blotting demonstrated that VacA intoxication increased syntaxin 7 mRNA and protein expression, respectively, in a time-dependent manner. Transient transfection of dominant-negative mutant syntaxin 7, which lacks a carboxyl-terminal transmembrane domain, inhibited VacA-induced vacuolation. In contrast, transient transfection of wild-type syntaxin 7, dominant-negative mutant syntaxin 1a, or dominant-negative mutant syntaxin 4 did not alter VacA-induced vacuolation. Furthermore, under VacA treatment, neutral red dye uptake, a parameter of VacA-induced vacuolation, was inhibited in cells stably transfected with mutant syntaxin 7 but not in cells stably transfected with wild-type syntaxin 7, mutant syntaxin 1a, or mutant syntaxin 4. Sequential immunocytochemical observation confirmed that expression of mutant syntaxin 7 did not affect VacA attachment to or internalization into AGS cells. We suggest that syntaxin 7 is involved in the intracellular vacuolation induced by VacA.
  • H Mashima, N Ueda, H Ohno, J Suzuki, H Ohnishi, H Yasuda, T Tsuchida, C Kanamaru, N Makita, T Iiri, M Omata, Kojima, I
    JOURNAL OF BIOLOGICAL CHEMISTRY 278 11 9520 - 9527 2003年03月 [査読有り][通常論文]
     
    Pancreatic AR42J cells have the feature of pluripotency of the precursor cells of the gut endoderm. Dexamethasone converts them to exocrine cells or liver cells. Using mRNA differential display techniques, we have identified a novel Ca2+-dependent member of the mitochondrial solute carrier superfamily, which is expressed during the course of differentiation, and have designated it MCSC. The corresponding cDNA comprises an open reading frame of 1407 base pairs encoding a polypeptide of 469 amino acids. The carboxyl-terminal-half of MCSC has high similarity with other mitochondrial carriers, and the amino-terminal-half has three canonical elongation factor-hand motifs and has calcium binding capacity. The deduced amino acid sequence revealed 79.1% homology to the rabbit peroxisomal Ca2+-dependent member of the mitochondrial superfamily, but the subcellular localization of the protein was exclusively mitochondrial, not peroxisomal. Northern blot and Western blot analyses revealed its predominant expression in the liver and the skeletal muscle. In the liver, the expression level of MCSC was higher in the adult stage than in the fetal stage, and MCSC was highly up-regulated in dexamethasone-treated AR42J cells before the expression of albumin. Taken together, MCSC may play an important role in regulating the function of hepatocytes rather than in differentiation in vivo.
  • SK Rasmussen, SA Urhammer, L Berglund, JN Jensen, L Hansen, SM Echwald, K Borch-Johnsen, Y Horikawa, H Mashima, H Lithell, NJ Cox, T Hansen, GI Bell, O Pedersen
    DIABETES 51 12 3561 - 3567 2002年12月 [査読有り][通常論文]
     
    Variations in the calpain-10 gene (CAPN10) have been identified among Mexican-Americans, and an at-risk haplotype combination (112/121) defined by three polymorphisms, UCSNP-43, -19, and -63, confers increased risk of type 2 diabetes. Here we examine the three polymorphisms in 1,594 -Scandinavian subjects, including 409 type 2 diabetic patients, 200 glucose-tolerant control subjects, 322 young healthy subjects, 206 glucose-tolerant offspring of diabetic patients, and 457 glucose-tolerant 70-year-old men. The frequency of the 112/121 combination was not significantly different in 409 type 2 diabetic subjects compared with 200 glucose-tolerant control subjects (0.06 vs. 0.05; odds ratio 1.32 [95% CI 0.58-3.30]). In glucose-tolerant subjects, neither the single-nucleotide polymorphisms individually nor the 112/121 combination were associated with alterations in plasma glucose, serum insulin, or serum C-peptide levels at fasting or during an oral glucose tolerance test, estimates of insulin sensitivity, or glucose-induced insulin secretion. In conclusion, the frequency of the 112/121 at-risk haplotype of CAPN10 is low among Scandinavians and we were unable to demonstrate significant associations between the CAPN10 variants and type 2 diabetes, insulin resistance, or impaired insulin secretion.
  • Dynamin is involved in human epithelial cell vacuolation caused by the pylori-induced cytotoxin VacA.
    Suzuki J, Ohnishi H, Shibata H, Wada A, Hirayama T, Iiri T, Ueda N, Kanamaru C, Tsuchida T, Mashima H, Yasuda H, Fujita T
    J. Clin. Invest. 107 363 - 370 2001年 [査読有り][通常論文]
  • 眞嶋 浩聡
    J. Biol. Chem. 276 45636 - 45641 2001年 [査読有り][通常論文]
  • N Ueda, H Ohnishi, C Kanamaru, J Suzuki, T Tsuchida, H Mashima, H Yasuda, T Fujita
    GASTROENTEROLOGY 119 4 1123 - 1131 2000年10月 [査読有り][通常論文]
     
    Background & Aims: Kinesin has recently been localized to zymogen granules of pancreatic acini and is suggested to participate in exocytosis of exocrine pancreas, We examined the function of kinesin in regulated exocytosis of pancreatic acini in this study, Methods: Kinesin function in exocytosis was examined by introducing hexahistidine-tagged recombinant kinesin protein and antikinesin monoclonal antibody into streptolysin-O-permeabilized acini. Intracellular localization of introduced recombinant kinesin was investigated by immunohistochemistry. Interaction between recombinant kinesin and the microtubule network was confirmed by nocodazole pretreatment of acini, Kinesin regulation by secretagogues was investigated by examining their effect on adenosine triphosphatase (ATPase) activity of endogenous kinesin, Results: Recombinant kinesin enhanced calcium-stimulated amylase release from streptolysin-O-permeabilized acini, Introduced recombinant kinesin was localized to both the microtubule network and zymogen granule, Nocodazole pretreatment of acini abolished the enhancing effect of recombinant kinesin on calcium-stimulated amylase release. Antikinesin antibody inhibited amylase release stimulated by the combination of calcium and cyclic adenosine monophosphate (cAMP) but not that stimulated by calcium alone, Secretin and 8-bromo-cAMP increased ATPase activity of endogenous kinesin. Conclusions: Kinesin plays a stimulatory role in regulated exocytosis of pancreatic acini and is involved in stimulus-secretion coupling through a cAMP-dependent pathway.
  • Genetic variation in the calpain 10 gene (CAPN10) affects susceptibility to type 2 diabetes in Mexican Americans.
    眞嶋 浩聡
    Nat Genet 26 163 - 175 2000年 [査読有り][通常論文]
  • H Mashima, S Yamada, T Tajima, M Seno, H Yamada, J Takeda, Kojima, I
    DIABETES 48 2 304 - 309 1999年02月 [査読有り][通常論文]
     
    dPancreatic AR42J cells have the feature of pluripotency of the common precursor cells of the pancreas. Dexamethasone (Dx) converts them to exocrine cells, whereas activin A (Act) converts them into endocrine cells expressing pancreatic polypeptide. A combination of Act and betacellulin (BTC) converts them further into insulin-secreting cells, The present study identifies some of the genes involved in the process of differentiation that is induced by these factors, using the mRNA differential display and screening of the cDNA expression array. The expression levels of 7 genes were increased by Act alone, and a combination of Act and ETC increased the expression of 25 more genes. Of these, 16 represented known genes or homologues of genes characterized previously, Nine of the identified genes were unrelated to any other sequences in the database. An inhibitor of the mitogen-activated protein kinase pathway, PD098059, which blocks the differentiation into insulin-secreting cells, inhibited the expression of 18 of the 25 genes, suggesting that the proteins encoded by these genes are associated with the differentiation into insulin-producing cells, These include known genes encoding extracellular signaling molecules, such as parathyroid hormone-related peptide, cyloskeletal proteins, and intracellular signaling molecules. Identification and characterization of these differentially expressed genes should help to clarify the molecular mechanism of differentiation of pancreatic cells and the; gene products that enable the beta-cells to produce insulin.
  • Translocation of a calcium-permeable cation channel induced by insulin-like growth factor-1.
    眞嶋 浩聡
    Nat Cell Biol 1 165 - 170 1999年 [査読有り][通常論文]
  • YQ Zhang, H Mashima, M Kanzaki, H Shibata, Kojima, I
    HEPATOLOGY 25 6 1370 - 1375 1997年06月 [査読有り][通常論文]
     
    The present study was conducted to determine the role of two autocrine factors, activin A and transforming growth factor beta (TGF-beta), in the growth regulation of AML12 hepatocytes, me overexpressed truncated type II activin and/or TGF-beta receptors in AML12 cells, In AML12 cells overexpressing truncated type II activin receptors (AML-tAR cells), the inhibitory effect of activin A on DNA synthesis was completely blocked, AML-tAR cells proliferated faster than parental cells, both in the presence and absence of epidermal growth factor (EGF). However, AML-tAR cells could not grow in soft agar. Fol listatin augmented EGF-induced DNA synthesis in AML12 cells, whereas it was ineffective in AML-tAR cells, In AML12 cells overexpressing truncated type II TGF-beta receptor (AML-tTR cells), the inhibitory effect of TGF-beta on DNA synthesis was blocked. AML-tTR cells proliferated faster than parental cells, both in the presence and absence of EGF, but at a slower rate than that of AML-tAR cells, AML-tTR cells did not grow in soft agar. The growth rate of cells overexpressing both types of truncated receptors was identical to that of AML-tAR cells, and these cells did not grow in soft agar, These results indicate that both activin A and TGF-beta act as autocrine inhibitors of DNA synthesis in AML12 cells, and that the blocking of the actions of two factors does not lead to transformation. Activin A is a predominant autocrine factor in these cells.
  • YQ Zhang, M Kanzaki, H Mashima, T Mine, Kojima, I
    HEPATOLOGY 24 2 446 - 450 1996年08月 [査読有り][通常論文]
     
    Activin A is an autocrine inhibitor of initiation of DNA synthesis in rat hepatocytes. The present study was conducted to characterize the cell-surface receptors for activin A in cultured rat hepatocytes by measuring I-125-activin A binding, Scatchard analysis of I-125-activin A binding indicated the existence of two classes of binding sites with apparent Ma values of 3 x 10(-10) mol/L and 3.5 x 10(-9) mol/L. Pretreatment of the cells with heparitinase reduced the number of low-affinity binding sites, whereas pretreatment with excess exogenous follistatin increased the number of low-affinity binding sites. Affinity cross-linking of I-125-activin A to hepatocytes-revealed distinct protein complexes with molecular weights of approximately 48, 65, and 85 kd, which may represent cross-linked cell-bound follistatin, type I and type II activin receptors, respectively, Another band with a molecular weight of 180 kd was also found, which may represent the type III activin receptor. When hepatocytes were cultured with epidermal growth factor (EGF), both high- and low-affinity binding sites increased at 12 hours without altering their affinities, At 60 hours of the incubation with EGF, the high-affinity binding sites decreased while the number of low-affinity binding sites increased slightly. These results indicate that two classes of I-125-activin A binding sites exist in cultured hepatocytes: the high-affinity binding site may represent oligomeric complex of the type I and type II receptors, and at least part of the low-affinity binding site may represent cell-bound follistatin. The number of activin receptors in hepatocytes is increased after the stimulation with EGF.
  • H Mashima, H Ohnishi, K Wakabayashi, T Mine, J Miyagawa, T Hanafusa, M Seno, H Yamada, Kojima, I
    JOURNAL OF CLINICAL INVESTIGATION 97 7 1647 - 1654 1996年04月 [査読有り][通常論文]
     
    Rat pancreatic AR42J cells possess exocrine and neuroendocrine properties, Activin A induces morphological changes and converts them into neuron-like cells. In activin-treated cells, mRNA for pancreatic polypeptide (PP) but not that for either insulin or glucagon was detected by reverse transcription-PCR. About 25% of the cells were stained by anti-PP antibody. When AR42J cells were incubated with betacellulin, a small portion of the cells were stained positively with antiinsulin and anti-PP antibodies, The effect of betacellulin was dose dependent, being maximal at 2 nM, Approximately 4% of the cells became insulin positive at this concentration, and mRNAs for insulin and PP were detected. When AR42J cells were incubated with a combination of betacellulin and activin A, similar to 10% of the cells became insulin positive, Morphologically, the insulin-positive cells were composed of two types of cells: neuron-like and round-shaped cells, Immunoreactive PP was found in the latter type of cells, The mRNAs for insulin, PP, glucose transporter 2, and glucokinase, but not glucagon, were detected, Depolarizing concentration of potassium, tolbutamide, carbachol, and glucagon-like peptide-1 stimulated the release of immunoreactive insulin, These results indicate that betacellulin and activin A convert amylase-secreting AR42J cells into cells secreting insulin. AR42J cells provide a model system to study the formation of pancreatic endocrine cells.
  • YQ Zhang, M Kanzaki, H Mashima, T Mine, Kojima, I
    HEPATOLOGY 23 2 288 - 293 1996年02月 [査読有り][通常論文]
     
    Activin A, an autocrine factor produced by hepatocytes, inhibits mitogen-stimulated DNA synthesis and induces apoptotic death of cultured rat hepatocytes. Several lines of evidence indicate that norepinephrine (NE), as a comitogenic growth factor, alters the balance between growth stimulation and inhibition and acts as a trigger for the initiation of hepatocyte proliferation. In the present study, we examined whether NE modulated the effects of activin A on rat hepatocytes in primary culture. Activin A, at a concentration of 10(-9) mol/L, blocked the effect of epidermal growth factor (EGF) on DNA synthesis, that was assessed by measuring [H-3] thymidine incorporation and nuclear labeling, almost completely, and NE reversed the inhibitory effect of activin A on DNA synthesis. This effect of NE was dose-dependent, being significant at concentrations of 10(-6) mol/L and above, but was overcome by higher concentrations of activin A, and was attenuated by prazosin, but not by yohimbine or propranolol. NE exerted its effect during the first 24 hours of culture, but was ineffective when added after 24 hours. EGF augmented the release of follistatin, an activin-binding protein known to block the action of activin A, by hepatocytes and NE did not affect the amount of follistatin they released In addition to inhibiting DNA synthesis by hepatocytes cultured with EGF, activin A induced death of hepatocytes cultured in the absence of EGF. The nuclear morphology of cells cultured with activin A alone was strikingly changed compared with untreated control cells and marked identation of the nuclear membranes and moderate chromatin condensation were observed. Fragmentation of DNA was also observed, suggesting that activin A induced apoptosis, and activin-mediated cell death was prevented significantly by NE. These results indicate that NE, acting on alpha(1)-adrenergic receptors, attenuates the effects of activin A on DNA synthesis by and apoptosis of cultured rat hepatocytes.
  • 眞嶋 浩聡
    Endocrinology 137 3969 - 3976 1996年 [査読有り][通常論文]
  • H OHNISHI, N OHGUSHI, S TANAKA, H MOGAMI, R NOBUSAWA, H MASHIMA, M FURUKAWA, T MINE, O SHIMADA, H ISHIKAWA, KOJIMA, I
    JOURNAL OF CLINICAL INVESTIGATION 95 5 2304 - 2314 1995年05月 [査読有り][通常論文]
     
    When AR42J cells, an amylase-secreting pancreatic exocrine cell line, were treated with activin A, cells extended neuritelike processes, and, concomitantly, amylase-containing vesicles disappeared, Immunofluorescence and immunoelectron microscopy revealed that these processes had neurite-specific cytoskeletal architectures: neurofilaments and microtubule bundles with cross-bridges of microtubule-associated protein 2, In addition to such morphological changes, activin-treated cells exhibited a marked increase in cytoplasmic free calcium concentration in response to depolarizing concentration of potassium, Moreover, activin-treated AR42J cells expressed mRNA for alpha(1) subunit of the neuroendocrine/beta cell-type voltage-dependent calcium channel, In naive AR42J cells, a sulfonylurea compound, tolbutamide, did not affect free calcium concentration, while it induced a marked elevation of free calcium in activin-treated cells, Single channel recording of the membrane patch revealed the existence of ATP-sensitive potassium channel in activin-treated cells, These results indicate that activin A converts amylase-secreting AR42J cells to neuronlike cells, Given that pancreatic endocrine cells possess neuronlike properties and express ATP-sensitive potassium channel as well as neuroendocrine/beta cell-type voltage-dependent calcium channel, activin treatment of AR42J cells may provide an in vitro model system to study the conversion of pancreatic exocrine cells to endocrine cells in islets.
  • H MASHIMA, M KANZAKI, R NOBUSAWA, YQ ZHANG, M SUZUKI, T MINE, KOJIMA, I
    GASTROENTEROLOGY 108 3 834 - 840 1995年03月 [査読有り][通常論文]
     
    Background/Aims: The growth of normal hepatocytes is regulated by the activin-follistatin system. The aim of this study was to investigate the activin-follistatin system in hepatoma cells. Methods: The production and action of activin and follistatin in human hepatoma cell lines were examined. Activin A and follistatin were measured by bioassay and protein-binding assay, respectively. Results: Activin A inhibited cell growth in HepG2 cells but not in either PLC/PRF/5 or HLE cells. However, the effect of activin A in HepG2 cells was attenuated at high cell density. In HepG2 cells, two classes of activin-binding sites were expressed, and affinity cross-linking showed that I-125-activin A bound specifically to three proteins with molecular weights of 48, 67, and 94 kilodaltons. In PLC/PRF/5 cells, a single class of binding site was observed, and the binding capacity was approximately 60% of the capacity in HepG2 cells. Virtually no I-125-activin A binding was detected in HLE cells. Bioactivity and messenger RNA for activin A were undetectable in three cell lines. In contrast, follistatin was released from three cell lines. Conclusions: Multiple alterations in the activin-follistatin system were found in three hepatoma cell lines. The accelerated growth observed in hepatoma cells may be caused, at least partly, by the attenuation of the action of activin A.
  • Production of activin A in a human intestinal epithelial cell line.
    Kawamura N, Nobusawa R, Mashima H, Kanzaki M, Shibata H, Kojima I
    Dig. Dis. Sci. 40 2280 - 2285 1995年 [査読有り][通常論文]
  • Activin A: negative regulator of amylase secretion and cell proliferation in rat pancreatic acinar AR42J cells.
    Yasuda H, Tanaka S, Ohnishi H, Mashima H, Ogushi N, Mine T, Kojima I
    Am J Physiol-Gastroint Liver Physiol 267 G220 - G226 1994年 [査読有り][通常論文]

書籍

  • 関根 匡成, 胆膵EUS教本作成委員会, 大西 洋英 ()
    へるす出版 2018年04月 ISBN: 4892699446 66
  • 泉井 亮, 妹尾 春樹, 金田 研司, 安田 宏, 眞嶋 浩聡, 大野 秀樹 (担当:共著)
    日本医事新報社 2017年02月 ISBN: 4784932216 84
  • 今日の治療指針
    眞嶋 浩聡 (担当:分担執筆範囲:慢性膵炎)
    医学書院 2017年01月
  • MR研修テキスト(公益財団法人MR認定センター教育研修委員会監修)
    眞嶋 浩聡 (担当:分担執筆範囲:II 疾病と治療2012 臨床 消化器がん(食道・胃・大腸・肝・胆・膵))
    南山堂 2012年
  • 内科学 (門脇孝,永井良三編)
    眞嶋 浩聡 (担当:分担執筆範囲:胃・十二指腸潰瘍)
    西村書店 2012年
  • 消化器内科レジデントマニュアル第2版 (東京大学消化器内科編)
    眞嶋 浩聡 (担当:分担執筆範囲:Crohn病,腸結核)
    医学書院 2009年
  • Common Disease - Genetic and Pathogenetic Aspects of Multifactorial Diseases
    Bell G-I, Cox N-J, Daniel J-C, Bosque-Plata L, Fajans S-S, Hara M, Horikawa Y, Horikawa Y, Iwamoto Y, Iwasaki N, Li X, Mashima H, Njolstad P-R, Ogata M, Patterson B, Paz V-P, Polonsky K-S, So W-Y, Wang X, Ye (担当:共著範囲:Maturity-onset diabetes of the young - a model for genetic studies of diabetes mellitus)
    Uehara Memorial Foundation Symposium-1999 1999年
  • Inhibin, activin and follistatin.
    Kojima I, Mashima H, Ohnishi H, Furukawa M (担当:共著範囲:Effect of activin A on the formation of pancreatic endocrine cells)
    Serono Symposia USA 1997年

講演・口頭発表等

  • 直腸癌術後吻合部完全閉塞に対し内視鏡的拡張術を施行した1例  [通常講演]
    三浦 孝也, 関根 匡成, 森野 美奈, 松本 圭太, 賀嶋 ひとみ, 小糸 雄大, 高橋 裕子, 坪井 瑠美子, 石井 剛弘, 藤原 純一, 上原 健志, 浦吉 俊輔, 湯橋 一仁, 浅野 岳晴, 松本 吏弘, 鷺原 規喜, 宮谷 博幸, 眞嶋 浩聡
    Progress of Digestive Endoscopy 2018年06月
  • 主膵管拡張を契機に上皮内癌が疑われ、膵切除術を施行したPanIN-2の2症例  [通常講演]
    関根 匡成, 宮谷 博幸, 野田 弘志, 力山 敏樹, 大西 洋英, 眞嶋 浩聡
    膵臓 2018年05月
  • 経過観察中に穿孔部位の明らかでない腹膜炎を発症したDegos病(悪性萎縮性丘疹症)の1例  [通常講演]
    高澤 摩耶, 山田 真嗣, 塚原 理恵子, 梅本 尚可, 川瀬 正昭, 小宮根 真弓, 出光 俊郎, 山下 武志, 眞嶋 浩聡
    日本皮膚科学会雑誌 2018年05月
  • 低分子量Gタンパク質Rab7の膵外分泌腺における機能解析  [通常講演]
    高橋 健一, 眞嶋 浩聡, 大西 洋英
    膵臓 2018年05月
  • 基礎研究から紐解く膵・胆道の恒常性とその破綻 膵外分泌腺恒常性維持におけるRab7機能の検討  [通常講演]
    高橋 健一, 眞嶋 浩聡, 大西 洋英
    日本消化器病学会雑誌 2018年04月
  • 大腸癌低侵襲治療の新展開 大腸ESDの難易度に関するスコアリングの構築  [通常講演]
    松本 吏弘, 眞嶋 浩聡, 宮谷 博幸
    日本消化器病学会雑誌 2018年04月
  • 当院においてESDを行った大腸SM癌 診断・治療成績・予後  [通常講演]
    石井 剛弘, 松本 吏弘, 森野 美奈, 松本 圭太, 賀嶋 ひとみ, 小糸 雄大, 高橋 裕子, 三浦 孝也, 坪井 瑠美子, 藤原 純一, 関根 匡成, 上原 健志, 浦吉 俊輔, 湯橋 一仁, 浅野 岳晴, 鷺原 規喜, 宮谷 博幸, 眞嶋 浩聡
    Gastroenterological Endoscopy 2018年04月
  • 地方病院で始めた早期胃癌に対する内視鏡的粘膜下層剥離術師におけるラーニングカーブの検討  [通常講演]
    藤原 純一, 松本 吏弘, 鷺原 規喜, 浅野 岳晴, 湯橋 一仁, 浦吉 俊輔, 上原 健志, 関根 匡成, 石井 剛弘, 坪井 瑠美子, 高橋 裕子, 三浦 孝也, 小糸 雄大, 賀嶋 ひとみ, 松本 圭太, 眞嶋 浩聡, 安次嶺 拓馬
    Gastroenterological Endoscopy 2018年04月
  • 当科における大腸SM癌の術前深達度診断精度  [通常講演]
    三浦 孝也, 松本 吏弘, 森野 美奈, 松本 圭太, 賀嶋 ひとみ, 小糸 雄大, 高橋 裕子, 坪井 瑠美子, 石井 剛弘, 藤原 純一, 関根 匡成, 上原 健志, 浦吉 俊輔, 湯橋 一仁, 浅野 岳晴, 鷺原 規喜, 宮谷 博幸, 眞嶋 浩聡
    Gastroenterological Endoscopy 2018年04月
  • 内視鏡的処置時に鉗子口からの処置具の急な突出を防ぐためのアイデア-「カラーテープ仁丹法」の応用  [通常講演]
    松本 博成, 石田 茂夫, 宮谷 博幸, 眞嶋 浩聡
    埼玉県医学会雑誌 2017年12月
  • SHOULD EMERGENCY ENDOSCOPY BE PERFORMED IN ALL PATIENTS WITH SUSPECTED COLONIC DIVERTICULAR HEMORRHAGE?  [通常講演]
    Uehara T, Matsumoto S, Morino M, Matsumoto K, Kashima H, Takahashi Y, Ishii T, Sekine M, Urayoshi S, Yamanaka K, Asano T, Asabe S, Sagihara N, Miyatani H, Mashima H
    Digestive Disease Week 2017 2017年05月 ポスター発表
  • THE ROLE OF Gαq/Gα11 SIGNALING IN A RAT INTESTINAL EPITHELIAL CELL.  [通常講演]
    Mashima H, Watanabe N, Sekine M, Asano T, Uehara T, Urayoshi S, Yamanaka K, Matsumoto S, Sagihara N, Asabe S, Miyatani H, Ohnishi H
    Digestive Disease Week 2017 2017年05月 ポスター発表
  • RAB7 LOCALIZES TO ZYMOGEN GRANULE MEMBRANE IN PANCREATIC ACINAR CELLS AND CONTRIBUTES TO MATURATION OF ZYMOGEN GRANULES BUT NOT TO EXOCYTOSIS.  [通常講演]
    Takahashi K, Mashima H, Miura K, Goto T, Ohnishi H
    Digestive Disease Week 2017 2017年05月 ポスター発表
  • Exacerbation of the caerulein-induced acute pancreatitis in the pancreas-specific Rab7 knockout mice.  [通常講演]
    Takahashi K, Mashima H, Ohnishi H
    The Joint Conference of the 47th annual meeting of the Japan Pancreas Society (JPS), the 20th meeting of the International Association of Pancreatology (IAP) and the 6th meeting of the Asian Oceanic Pancreatic Association (AOPA). 2016年08月 口頭発表(一般)
  • Requirement of Gαq/Gα11 Signaling in the Preservation of Mouse Intestinal Epithelial Homeostasis.  [通常講演]
    Watanabe N, Mashima H, Miura K, Ohnishi H
    Digestive Disease Week 2016 2016年05月 口頭発表(一般)
  • Disruption of Small GTPase Rab7 Exacerbates the Severity of Caerulein-Induced Mouse Acute Pancreatitis.  [通常講演]
    Takahashi K, Mashima H, Maeda D, Goto A, Miura K, Goto T, Ohnishi H
    Digestive Disease Week 2016 2016年05月 ポスター発表
  • 大動脈炎症候群に合併したクローン病の1例  [通常講演]
    鷺原 規喜, 井上 依里, 矢部 寛樹, 賀嶋 ひとみ, 小糸 雄大, 石井 剛弘, 坪井 瑠美子, 田村 洋行, 上原 健志, 大竹 はるか, 池田 正俊, 新藤 雄司, 川村 晴水, 西川 剛司, 大滝 雄造, 浦吉 俊輔, 山中 健一, 牛丸 信也, 浅野 岳晴, 岩城 孝明, 松本 吏弘, 浅部 伸一, 宮谷 博幸, 田中 裕一, 野首 光弘, 眞嶋 浩聡
    自治医科大学紀要 2016年03月 
    31歳女性。大動脈炎症候群の治療中に、血便を認め当センターに入院した。下部消化管内視鏡検査にて、終末回腸に縦走潰瘍を認め、小腸型クローン病と診断した。寛解導入療法として、栄養療法とメサラジン製剤の内服に加え、生物学的製剤アダリムマブを投与した。寛解を得た後、プレドニゾロン・メトトレキセートの減量を行ったが、両疾患とも再燃・悪化なく経過している。両疾患の合併は稀であり、本邦からの報告例が19例、国外からの報告例を加えると55例に過ぎない。発症の順序に規則性は認めない。今回貴重な症例を経験したので、文献的考察を加え、報告する。(著者抄録)
  • 二種類のカルシウム結合蛋白と急性膵炎の関連の検討  [通常講演]
    眞嶋 浩聡
    第46回日本膵臓学会大会 2015年06月 シンポジウム・ワークショップパネル(公募)
  • Involvement of the calcium-binding protein in the onset of acute pancreatitis.  [通常講演]
    Mashima H, Watanabe N, Arata E, Ohnishi H
    Digestive Disease Week 2015. 2015年05月 ポスター発表
  • INSL5 indicates a unique population of neuroendocrine cells in the colorectal epithelium.  [通常講演]
    Mashima H, Yamada Y, Sakai T, Ohnishi H
    Digestive Disease Week 2013 2013年05月 ポスター発表
  • The role of interferon regulatory factor (IRF)-1 and IRF-2 in the progression of human pancreatic cancer.  [通常講演]
    Sakai T, Mashima H, Yamada Y, Goto T, Ohnishi H
    Digestive Disease Week 2013 2013年05月 ポスター発表
  • INSL5は大腸内分泌細胞の特徴的なマーカーであり、直腸神経内分泌細胞の発症に関与している可能性がある。  [通常講演]
    眞嶋 浩聡
    第55回日本消化器病学会大会(JDDW2013) 2013年 シンポジウム・ワークショップパネル(公募)
  • Searching for the primary target of IRF2 in regulated exocytosis in the pancreas.  [通常講演]
    Mashima H, Ohnishi H
    Digestive Disease Week 2012 2012年05月
  • IRF2KOマウスを用いた急性膵炎原因遺伝子へのアプローチ  [通常講演]
    眞嶋 浩聡
    第43回日本膵臓学会大会 2012年 シンポジウム・ワークショップパネル(公募)
  • The pancreas of Irf2-/- mice presented a very early feature of acute pancreatitis and a milder response in cerulein-induced pancreatitis  [通常講演]
    Mashima H, Sato T, Horie Y, Ohteki T, Ohnishi H
    Digestive Disease Week 2011 2011年05月 ポスター発表
  • Functional roles of TGF-b1 in intestinal epithelial cells through different SMAD-dependent pathways.  [通常講演]
    Yamada Y, Mashima H, Ohnishi H
    Digestive Disease Week 2011 2011年05月 ポスター発表
  • MCP-1 inhibits DNA synthesis in rat pancreatic stellate cells.  [通常講演]
    Kamada K, Mashima H, Goto T, Ohnishi H
    Joint Meeting of the International Association of Pancreatology and the Japan Pancreas Society 2010年05月 ポスター発表
  • Interferon regulatory factor-2 plays a pivotal role in exocytosis in pancreatic acinar cells.  [通常講演]
    Mashima H, Sato T, Horie Y, Ohteki T, Ohnishi H
    Digestive Disease Week 2010 2010年05月 口頭発表(一般)
  • Up-regulation of JAM-1 in AR42J cells treated with activin A and betacellulin and the diabetic regenerating islets.  [通常講演]
    Mashima H, Yoshikumi Y, Ohnishi H
    The International Pancreatic Research Forum 2009年 ポスター発表
  • The Role of VAMP7 on VacA-induced Vacuolation.  [通常講演]
    Mashima H, Suzuki J, Yoshikumi Y, Ohno H, Omata M
    Digestive Disease Week 2007 2007年05月 ポスター発表
  • Analysis of the Homeobox gene Cdx1 and Cdx2 expression in VacA intoxicated RGM1 cells.  [通常講演]
    Suzuki J, Yoshikumi Y, Mashima H, Masao O
    Digestive Disease Week 2005 2005年05月 ポスター発表
  • Roles of CTPL/Sfxn3 and Sfxn Family Members in the Differentiation and Regeneration of Pancreatic Islet.  [通常講演]
    Yoshikumi Y, Mashima H, Ueda N, Ohno H, Suzuki J, Omata M
    Digestive Disease Week 2004 2004年05月 ポスター発表
  • A Novel Mitochondrial Ca2+-dependent Solute Carrier in the Liver Identified by mRNA Differential Display.  [通常講演]
    Mashima H, Ueda N, Ohno H, Suzuki J, Omata M
    Digestive Disease Week 2003 2003年05月 ポスター発表
  • Involvement of Syntaxin 7 in Human Gastric Epithelial Cell Vacuolation Induced by Helicobacter pylori-produced Cytotoxin VacA.  [通常講演]
    Suzuki J, Ohnishi H, Ohno H, Yoshikumi Y, Ueda N, Mashima H, Omata M
    Digestive Disease Week 2003 2003年05月 ポスター発表
  • Dynamin is Involved in Zymogen Granule Transport in Rat Pancreatic Acinar Cells.  [通常講演]
    Ueda N, Ohnishi H, Suzuki J, Ohno H, Mashima H, Omata M
    Digestive Disease Week 2003 2003年05月 口頭発表(一般)
  • Molecular cloning of differentiation -associated sodium dependent phosphate transporter (DNPI).  [通常講演]
    Mashima H, Kojima I
    1st International Conference on Control & Diseases of Sodium Dependent Transport Proteins & Ion Channels 1999年 ポスター発表
  • Identification of the Genes Associated with Differentiation of AR42J Cells into Insulin-secreting Cells.  [通常講演]
    Mashima H, Takeda J, Seno M, Yamada H, Kojima I
    Digestive Disease Week 1998 1998年05月 ポスター発表
  • Conversion by HGF of Pancreatic acinar AR42J cells to insulin-secreting cells.  [通常講演]
    Mashima H, Kojima I
    10th International Congress of Endocrinology 1996年 ポスター発表
  • Activin A and betacellulin convert pancreatic AR42J cells into insulin-secreting cells.  [通常講演]
    Mashima H, Kojima I
    Annual Meeting of American Diabetes Association 1996年 口頭発表(一般)

MISC

  • Daniel J Klionsky, Kotb Abdelmohsen, Akihisa Abe, Md Joynal Abedin, Hagai Abeliovich, Abraham Acevedo Arozena, Hiroaki Adachi, Christopher M Adams, Peter D Adams, Khosrow Adeli, Peter J Adhihetty, Sharon G Adler, Galila Agam, Rajesh Agarwal, Manish K Aghi, Maria Agnello, Patrizia Agostinis, Patricia V Aguilar, Julio Aguirre-Ghiso, Edoardo M Airoldi, Slimane Ait-Si-Ali, Takahiko Akematsu, Emmanuel T Akporiaye, Mohamed Al-Rubeai, Guillermo M Albaiceta, Chris Albanese, Diego Albani, Matthew L Albert, Jesus Aldudo, Hana Algül, Mehrdad Alirezaei, Iraide Alloza, Alexandru Almasan, Maylin Almonte-Beceril, Emad S Alnemri, Covadonga Alonso, Nihal Altan-Bonnet, Dario C Altieri, Silvia Alvarez, Lydia Alvarez-Erviti, Sandro Alves, Giuseppina Amadoro, Atsuo Amano, Consuelo Amantini, Santiago Ambrosio, Ivano Amelio, Amal O Amer, Mohamed Amessou, Angelika Amon, Zhenyi An, Frank A Anania, Stig U Andersen, Usha P Andley, Catherine K Andreadi, Nathalie Andrieu-Abadie, Alberto Anel, David K Ann, Shailendra Anoopkumar-Dukie, Manuela Antonioli, Hiroshi Aoki, Nadezda Apostolova, Saveria Aquila, Katia Aquilano, Koichi Araki, Eli Arama, Agustin Aranda, Jun Araya, Alexandre Arcaro, Esperanza Arias, Hirokazu Arimoto, Aileen R Ariosa, Jane L Armstrong, Thierry Arnould, Ivica Arsov, Katsuhiko Asanuma, Valerie Askanas, Eric Asselin, Ryuichiro Atarashi, Sally S Atherton, Julie D Atkin, Laura D Attardi, Patrick Auberger, Georg Auburger, Laure Aurelian, Riccardo Autelli, Laura Avagliano, Maria Laura Avantaggiati, Limor Avrahami, Suresh Awale, Neelam Azad, Tiziana Bachetti, Jonathan M Backer, Dong-Hun Bae, Jae-Sung Bae, Ok-Nam Bae, Soo Han Bae, Eric H Baehrecke, Seung-Hoon Baek, Stephen Baghdiguian, Agnieszka Bagniewska-Zadworna, Hua Bai, Jie Bai, Xue-Yuan Bai, Yannick Bailly, Kithiganahalli Narayanaswamy Balaji, Walter Balduini, Andrea Ballabio, Rena Balzan, Rajkumar Banerjee, Gábor Bánhegyi, Haijun Bao, Benoit Barbeau, Maria D Barrachina, Esther Barreiro, Bonnie Bartel, Alberto Bartolomé, Diane C Bassham, Maria Teresa Bassi, Robert C Bast Jr, Alakananda Basu, Maria Teresa Batista, Henri Batoko, Maurizio Battino, Kyle Bauckman, Bradley L Baumgarner, K Ulrich Bayer, Rupert Beale, Jean-François Beaulieu, George R Beck Jr, Christoph Becker, J David Beckham, Pierre-André Bédard, Patrick J Bednarski, Thomas J Begley, Christian Behl, Christian Behrends, Georg Mn Behrens, Kevin E Behrns, Eloy Bejarano, Amine Belaid, Francesca Belleudi, Giovanni Bénard, Guy Berchem, Daniele Bergamaschi, Matteo Bergami, Ben Berkhout, Laura Berliocchi, Amélie Bernard, Monique Bernard, Francesca Bernassola, Anne Bertolotti, Amanda S Bess, Sébastien Besteiro, Saverio Bettuzzi, Savita Bhalla, Shalmoli Bhattacharyya, Sujit K Bhutia, Caroline Biagosch, Michele Wolfe Bianchi, Martine Biard-Piechaczyk, Viktor Billes, Claudia Bincoletto, Baris Bingol, Sara W Bird, Marc Bitoun, Ivana Bjedov, Craig Blackstone, Lionel Blanc, Guillermo A Blanco, Heidi Kiil Blomhoff, Emilio Boada-Romero, Stefan Böckler, Marianne Boes, Kathleen Boesze-Battaglia, Lawrence H Boise, Alessandra Bolino, Andrea Boman, Paolo Bonaldo, Matteo Bordi, Jürgen Bosch, Luis M Botana, Joelle Botti, German Bou, Marina Bouché, Marion Bouchecareilh, Marie-Josée Boucher, Michael E Boulton, Sebastien G Bouret, Patricia Boya, Michaël Boyer-Guittaut, Peter V Bozhkov, Nathan Brady, Vania Mm Braga, Claudio Brancolini, Gerhard H Braus, José M Bravo-San Pedro, Lisa A Brennan, Emery H Bresnick, Patrick Brest, Dave Bridges, Marie-Agnès Bringer, Marisa Brini, Glauber C Brito, Bertha Brodin, Paul S Brookes, Eric J Brown, Karen Brown, Hal E Broxmeyer, Alain Bruhat, Patricia Chakur Brum, John H Brumell, Nicola Brunetti-Pierri, Robert J Bryson-Richardson, Shilpa Buch, Alastair M Buchan, Hikmet Budak, Dmitry V Bulavin, Scott J Bultman, Geert Bultynck, Vladimir Bumbasirevic, Yan Burelle, Robert E Burke, Margit Burmeister, Peter Bütikofer, Laura Caberlotto, Ken Cadwell, Monika Cahova, Dongsheng Cai, Jingjing Cai, Qian Cai, Sara Calatayud, Nadine Camougrand, Michelangelo Campanella, Grant R Campbell, Matthew Campbell, Silvia Campello, Robin Candau, Isabella Caniggia, Lavinia Cantoni, Lizhi Cao, Allan B Caplan, Michele Caraglia, Claudio Cardinali, Sandra Morais Cardoso, Jennifer S Carew, Laura A Carleton, Cathleen R Carlin, Silvia Carloni, Sven R Carlsson, Didac Carmona-Gutierrez, Leticia Am Carneiro, Oliana Carnevali, Serena Carra, Alice Carrier, Bernadette Carroll, Caty Casas, Josefina Casas, Giuliana Cassinelli, Perrine Castets, Susana Castro-Obregon, Gabriella Cavallini, Isabella Ceccherini, Francesco Cecconi, Arthur I Cederbaum, Valentín Ceña, Simone Cenci, Claudia Cerella, Davide Cervia, Silvia Cetrullo, Hassan Chaachouay, Han-Jung Chae, Andrei S Chagin, Chee-Yin Chai, Gopal Chakrabarti, Georgios Chamilos, Edmond Yw Chan, Matthew Tv Chan, Dhyan Chandra, Pallavi Chandra, Chih-Peng Chang, Raymond Chuen-Chung Chang, Ta Yuan Chang, John C Chatham, Saurabh Chatterjee, Santosh Chauhan, Yongsheng Che, Michael E Cheetham, Rajkumar Cheluvappa, Chun-Jung Chen, Gang Chen, Guang-Chao Chen, Guoqiang Chen, Hongzhuan Chen, Jeff W Chen, Jian-Kang Chen, Min Chen, Mingzhou Chen, Peiwen Chen, Qi Chen, Quan Chen, Shang-Der Chen, Si Chen, Steve S-L Chen, Wei Chen, Wei-Jung Chen, Wen Qiang Chen, Wenli Chen, Xiangmei Chen, Yau-Hung Chen, Ye-Guang Chen, Yin Chen, Yingyu Chen, Yongshun Chen, Yu-Jen Chen, Yue-Qin Chen, Yujie Chen, Zhen Chen, Zhong Chen, Alan Cheng, Christopher Hk Cheng, Hua Cheng, Heesun Cheong, Sara Cherry, Jason Chesney, Chun Hei Antonio Cheung, Eric Chevet, Hsiang Cheng Chi, Sung-Gil Chi, Fulvio Chiacchiera, Hui-Ling Chiang, Roberto Chiarelli, Mario Chiariello, Marcello Chieppa, Lih-Shen Chin, Mario Chiong, Gigi Nc Chiu, Dong-Hyung Cho, Ssang-Goo Cho, William C Cho, Yong-Yeon Cho, Young-Seok Cho, Augustine Mk Choi, Eui-Ju Choi, Eun-Kyoung Choi, Jayoung Choi, Mary E Choi, Seung-Il Choi, Tsui-Fen Chou, Salem Chouaib, Divaker Choubey, Vinay Choubey, Kuan-Chih Chow, Kamal Chowdhury, Charleen T Chu, Tsung-Hsien Chuang, Taehoon Chun, Hyewon Chung, Taijoon Chung, Yuen-Li Chung, Yong-Joon Chwae, Valentina Cianfanelli, Roberto Ciarcia, Iwona A Ciechomska, Maria Rosa Ciriolo, Mara Cirone, Sofie Claerhout, Michael J Clague, Joan Clària, Peter Gh Clarke, Robert Clarke, Emilio Clementi, Cédric Cleyrat, Miriam Cnop, Eliana M Coccia, Tiziana Cocco, Patrice Codogno, Jörn Coers, Ezra Ew Cohen, David Colecchia, Luisa Coletto, Núria S Coll, Emma Colucci-Guyon, Sergio Comincini, Maria Condello, Katherine L Cook, Graham H Coombs, Cynthia D Cooper, J Mark Cooper, Isabelle Coppens, Maria Tiziana Corasaniti, Marco Corazzari, Ramon Corbalan, Elisabeth Corcelle-Termeau, Mario D Cordero, Cristina Corral-Ramos, Olga Corti, Andrea Cossarizza, Paola Costelli, Safia Costes, Susan L Cotman, Ana Coto-Montes, Sandra Cottet, Eduardo Couve, Lori R Covey, L Ashley Cowart, Jeffery S Cox, Fraser P Coxon, Carolyn B Coyne, Mark S Cragg, Rolf J Craven, Tiziana Crepaldi, Jose L Crespo, Alfredo Criollo, Valeria Crippa, Maria Teresa Cruz, Ana Maria Cuervo, Jose M Cuezva, Taixing Cui, Pedro R Cutillas, Mark J Czaja, Maria F Czyzyk-Krzeska, Ruben K Dagda, Uta Dahmen, Chunsun Dai, Wenjie Dai, Yun Dai, Kevin N Dalby, Luisa Dalla Valle, Guillaume Dalmasso, Marcello D'Amelio, Markus Damme, Arlette Darfeuille-Michaud, Catherine Dargemont, Victor M Darley-Usmar, Srinivasan Dasarathy, Biplab Dasgupta, Srikanta Dash, Crispin R Dass, Hazel Marie Davey, Lester M Davids, David Dávila, Roger J Davis, Ted M Dawson, Valina L Dawson, Paula Daza, Jackie de Belleroche, Paul de Figueiredo, Regina Celia Bressan Queiroz de Figueiredo, José de la Fuente, Luisa De Martino, Antonella De Matteis, Guido Ry De Meyer, Angelo De Milito, Mauro De Santi, Wanderley de Souza, Vincenzo De Tata, Daniela De Zio, Jayanta Debnath, Reinhard Dechant, Jean-Paul Decuypere, Shane Deegan, Benjamin Dehay, Barbara Del Bello, Dominic P Del Re, Régis Delage-Mourroux, Lea Md Delbridge, Louise Deldicque, Elizabeth Delorme-Axford, Yizhen Deng, Joern Dengjel, Melanie Denizot, Paul Dent, Channing J Der, Vojo Deretic, Benoît Derrien, Eric Deutsch, Timothy P Devarenne, Rodney J Devenish, Sabrina Di Bartolomeo, Nicola Di Daniele, Fabio Di Domenico, Alessia Di Nardo, Simone Di Paola, Antonio Di Pietro, Livia Di Renzo, Aaron DiAntonio, Guillermo Díaz-Araya, Ines Díaz-Laviada, Maria T Diaz-Meco, Javier Diaz-Nido, Chad A Dickey, Robert C Dickson, Marc Diederich, Paul Digard, Ivan Dikic, Savithrama P Dinesh-Kumar, Chan Ding, Wen-Xing Ding, Zufeng Ding, Luciana Dini, Jörg Hw Distler, Abhinav Diwan, Mojgan Djavaheri-Mergny, Kostyantyn Dmytruk, Renwick Cj Dobson, Volker Doetsch, Karol Dokladny, Svetlana Dokudovskaya, Massimo Donadelli, X Charlie Dong, Xiaonan Dong, Zheng Dong, Terrence M Donohue Jr, Kelly S Doran, Gabriella D'Orazi, Gerald W Dorn 2nd, Victor Dosenko, Sami Dridi, Liat Drucker, Jie Du, Li-Lin Du, Lihuan Du, André du Toit, Priyamvada Dua, Lei Duan, Pu Duann, Vikash Kumar Dubey, Michael R Duchen, Michel A Duchosal, Helene Duez, Isabelle Dugail, Verónica I Dumit, Mara C Duncan, Elaine A Dunlop, William A Dunn Jr, Nicolas Dupont, Luc Dupuis, Raúl V Durán, Thomas M Durcan, Stéphane Duvezin-Caubet, Umamaheswar Duvvuri, Vinay Eapen, Darius Ebrahimi-Fakhari, Arnaud Echard, Leopold Eckhart, Charles L Edelstein, Aimee L Edinger, Ludwig Eichinger, Tobias Eisenberg, Avital Eisenberg-Lerner, N Tony Eissa, Wafik S El-Deiry, Victoria El-Khoury, Zvulun Elazar, Hagit Eldar-Finkelman, Chris Jh Elliott, Enzo Emanuele, Urban Emmenegger, Nikolai Engedal, Anna-Mart Engelbrecht, Simone Engelender, Jorrit M Enserink, Ralf Erdmann, Jekaterina Erenpreisa, Rajaraman Eri, Jason L Eriksen, Andreja Erman, Ricardo Escalante, Eeva-Liisa Eskelinen, Lucile Espert, Lorena Esteban-Martínez, Thomas J Evans, Mario Fabri, Gemma Fabrias, Cinzia Fabrizi, Antonio Facchiano, Nils J Færgeman, Alberto Faggioni, W Douglas Fairlie, Chunhai Fan, Daping Fan, Jie Fan, Shengyun Fang, Manolis Fanto, Alessandro Fanzani, Thomas Farkas, Mathias Faure, Francois B Favier, Howard Fearnhead, Massimo Federici, Erkang Fei, Tania C Felizardo, Hua Feng, Yibin Feng, Yuchen Feng, Thomas A Ferguson, Álvaro F Fernández, Maite G Fernandez-Barrena, Jose C Fernandez-Checa, Arsenio Fernández-López, Martin E Fernandez-Zapico, Olivier Feron, Elisabetta Ferraro, Carmen Veríssima Ferreira-Halder, Laszlo Fesus, Ralph Feuer, Fabienne C Fiesel, Eduardo C Filippi-Chiela, Giuseppe Filomeni, Gian Maria Fimia, John H Fingert, Steven Finkbeiner, Toren Finkel, Filomena Fiorito, Paul B Fisher, Marc Flajolet, Flavio Flamigni, Oliver Florey, Salvatore Florio, R Andres Floto, Marco Folini, Carlo Follo, Edward A Fon, Francesco Fornai, Franco Fortunato, Alessandro Fraldi, Rodrigo Franco, Arnaud Francois, Aurélie François, Lisa B Frankel, Iain Dc Fraser, Norbert Frey, Damien G Freyssenet, Christian Frezza, Scott L Friedman, Daniel E Frigo, Dongxu Fu, José M Fuentes, Juan Fueyo, Yoshio Fujitani, Yuuki Fujiwara, Mikihiro Fujiya, Mitsunori Fukuda, Simone Fulda, Carmela Fusco, Bozena Gabryel, Matthias Gaestel, Philippe Gailly, Malgorzata Gajewska, Sehamuddin Galadari, Gad Galili, Inmaculada Galindo, Maria F Galindo, Giovanna Galliciotti, Lorenzo Galluzzi, Luca Galluzzi, Vincent Galy, Noor Gammoh, Sam Gandy, Anand K Ganesan, Swamynathan Ganesan, Ian G Ganley, Monique Gannagé, Fen-Biao Gao, Feng Gao, Jian-Xin Gao, Lorena García Nannig, Eleonora García Véscovi, Marina Garcia-Macía, Carmen Garcia-Ruiz, Abhishek D Garg, Pramod Kumar Garg, Ricardo Gargini, Nils Christian Gassen, Damián Gatica, Evelina Gatti, Julie Gavard, Evripidis Gavathiotis, Liang Ge, Pengfei Ge, Shengfang Ge, Po-Wu Gean, Vania Gelmetti, Armando A Genazzani, Jiefei Geng, Pascal Genschik, Lisa Gerner, Jason E Gestwicki, David A Gewirtz, Saeid Ghavami, Eric Ghigo, Debabrata Ghosh, Anna Maria Giammarioli, Francesca Giampieri, Claudia Giampietri, Alexandra Giatromanolaki, Derrick J Gibbings, Lara Gibellini, Spencer B Gibson, Vanessa Ginet, Antonio Giordano, Flaviano Giorgini, Elisa Giovannetti, Stephen E Girardin, Suzana Gispert, Sandy Giuliano, Candece L Gladson, Alvaro Glavic, Martin Gleave, Nelly Godefroy, Robert M Gogal Jr, Kuppan Gokulan, Gustavo H Goldman, Delia Goletti, Michael S Goligorsky, Aldrin V Gomes, Ligia C Gomes, Hernando Gomez, Candelaria Gomez-Manzano, Rubén Gómez-Sánchez, Dawit Ap Gonçalves, Ebru Goncu, Qingqiu Gong, Céline Gongora, Carlos B Gonzalez, Pedro Gonzalez-Alegre, Pilar Gonzalez-Cabo, Rosa Ana González-Polo, Ing Swie Goping, Carlos Gorbea, Nikolai V Gorbunov, Daphne R Goring, Adrienne M Gorman, Sharon M Gorski, Sandro Goruppi, Shino Goto-Yamada, Cecilia Gotor, Roberta A Gottlieb, Illana Gozes, Devrim Gozuacik, Yacine Graba, Martin Graef, Giovanna E Granato, Gary Dean Grant, Steven Grant, Giovanni Luca Gravina, Douglas R Green, Alexander Greenhough, Michael T Greenwood, Benedetto Grimaldi, Frédéric Gros, Charles Grose, Jean-Francois Groulx, Florian Gruber, Paolo Grumati, Tilman Grune, Jun-Lin Guan, Kun-Liang Guan, Barbara Guerra, Carlos Guillen, Kailash Gulshan, Jan Gunst, Chuanyong Guo, Lei Guo, Ming Guo, Wenjie Guo, Xu-Guang Guo, Andrea A Gust, Åsa B Gustafsson, Elaine Gutierrez, Maximiliano G Gutierrez, Ho-Shin Gwak, Albert Haas, James E Haber, Shinji Hadano, Monica Hagedorn, David R Hahn, Andrew J Halayko, Anne Hamacher-Brady, Kozo Hamada, Ahmed Hamai, Andrea Hamann, Maho Hamasaki, Isabelle Hamer, Qutayba Hamid, Ester M Hammond, Feng Han, Weidong Han, James T Handa, John A Hanover, Malene Hansen, Masaru Harada, Ljubica Harhaji-Trajkovic, J Wade Harper, Abdel Halim Harrath, Adrian L Harris, James Harris, Udo Hasler, Peter Hasselblatt, Kazuhisa Hasui, Robert G Hawley, Teresa S Hawley, Congcong He, Cynthia Y He, Fengtian He, Gu He, Rong-Rong He, Xian-Hui He, You-Wen He, Yu-Ying He, Joan K Heath, Marie-Josée Hébert, Robert A Heinzen, Gudmundur Vignir Helgason, Michael Hensel, Elizabeth P Henske, Chengtao Her, Paul K Herman, Agustín Hernández, Carlos Hernandez, Sonia Hernández-Tiedra, Claudio Hetz, P Robin Hiesinger, Katsumi Higaki, Sabine Hilfiker, Bradford G Hill, Joseph A Hill, William D Hill, Keisuke Hino, Daniel Hofius, Paul Hofman, Günter U Höglinger, Jörg Höhfeld, Marina K Holz, Yonggeun Hong, David A Hood, Jeroen Jm Hoozemans, Thorsten Hoppe, Chin Hsu, Chin-Yuan Hsu, Li-Chung Hsu, Dong Hu, Guochang Hu, Hong-Ming Hu, Hongbo Hu, Ming Chang Hu, Yu-Chen Hu, Zhuo-Wei Hu, Fang Hua, Ya Hua, Canhua Huang, Huey-Lan Huang, Kuo-How Huang, Kuo-Yang Huang, Shile Huang, Shiqian Huang, Wei-Pang Huang, Yi-Ran Huang, Yong Huang, Yunfei Huang, Tobias B Huber, Patricia Huebbe, Won-Ki Huh, Juha J Hulmi, Gang Min Hur, James H Hurley, Zvenyslava Husak, Sabah Na Hussain, Salik Hussain, Jung Jin Hwang, Seungmin Hwang, Thomas Is Hwang, Atsuhiro Ichihara, Yuzuru Imai, Carol Imbriano, Megumi Inomata, Takeshi Into, Valentina Iovane, Juan L Iovanna, Renato V Iozzo, Nancy Y Ip, Javier E Irazoqui, Pablo Iribarren, Yoshitaka Isaka, Aleksandra J Isakovic, Harry Ischiropoulos, Jeffrey S Isenberg, Mohammad Ishaq, Hiroyuki Ishida, Isao Ishii, Jane E Ishmael, Ciro Isidoro, Ken-Ichi Isobe, Erika Isono, Shohreh Issazadeh-Navikas, Koji Itahana, Eisuke Itakura, Andrei I Ivanov, Anand Krishnan V Iyer, José M Izquierdo, Yotaro Izumi, Valentina Izzo, Marja Jäättelä, Nadia Jaber, Daniel John Jackson, William T Jackson, Tony George Jacob, Thomas S Jacques, Chinnaswamy Jagannath, Ashish Jain, Nihar Ranjan Jana, Byoung Kuk Jang, Alkesh Jani, Bassam Janji, Paulo Roberto Jannig, Patric J Jansson, Steve Jean, Marina Jendrach, Ju-Hong Jeon, Niels Jessen, Eui-Bae Jeung, Kailiang Jia, Lijun Jia, Hong Jiang, Hongchi Jiang, Liwen Jiang, Teng Jiang, Xiaoyan Jiang, Xuejun Jiang, Xuejun Jiang, Ying Jiang, Yongjun Jiang, Alberto Jiménez, Cheng Jin, Hongchuan Jin, Lei Jin, Meiyan Jin, Shengkan Jin, Umesh Kumar Jinwal, Eun-Kyeong Jo, Terje Johansen, Daniel E Johnson, Gail Vw Johnson, James D Johnson, Eric Jonasch, Chris Jones, Leo Ab Joosten, Joaquin Jordan, Anna-Maria Joseph, Bertrand Joseph, Annie M Joubert, Dianwen Ju, Jingfang Ju, Hsueh-Fen Juan, Katrin Juenemann, Gábor Juhász, Hye Seung Jung, Jae U Jung, Yong-Keun Jung, Heinz Jungbluth, Matthew J Justice, Barry Jutten, Nadeem O Kaakoush, Kai Kaarniranta, Allen Kaasik, Tomohiro Kabuta, Bertrand Kaeffer, Katarina Kågedal, Alon Kahana, Shingo Kajimura, Or Kakhlon, Manjula Kalia, Dhan V Kalvakolanu, Yoshiaki Kamada, Konstantinos Kambas, Vitaliy O Kaminskyy, Harm H Kampinga, Mustapha Kandouz, Chanhee Kang, Rui Kang, Tae-Cheon Kang, Tomotake Kanki, Thirumala-Devi Kanneganti, Haruo Kanno, Anumantha G Kanthasamy, Marc Kantorow, Maria Kaparakis-Liaskos, Orsolya Kapuy, Vassiliki Karantza, Md Razaul Karim, Parimal Karmakar, Arthur Kaser, Susmita Kaushik, Thomas Kawula, A Murat Kaynar, Po-Yuan Ke, Zun-Ji Ke, John H Kehrl, Kate E Keller, Jongsook Kim Kemper, Anne K Kenworthy, Oliver Kepp, Andreas Kern, Santosh Kesari, David Kessel, Robin Ketteler, Isis do Carmo Kettelhut, Bilon Khambu, Muzamil Majid Khan, Vinoth Km Khandelwal, Sangeeta Khare, Juliann G Kiang, Amy A Kiger, Akio Kihara, Arianna L Kim, Cheol Hyeon Kim, Deok Ryong Kim, Do-Hyung Kim, Eung Kweon Kim, Hye Young Kim, Hyung-Ryong Kim, Jae-Sung Kim, Jeong Hun Kim, Jin Cheon Kim, Jin Hyoung Kim, Kwang Woon Kim, Michael D Kim, Moon-Moo Kim, Peter K Kim, Seong Who Kim, Soo-Youl Kim, Yong-Sun Kim, Yonghyun Kim, Adi Kimchi, Alec C Kimmelman, Tomonori Kimura, Jason S King, Karla Kirkegaard, Vladimir Kirkin, Lorrie A Kirshenbaum, Shuji Kishi, Yasuo Kitajima, Katsuhiko Kitamoto, Yasushi Kitaoka, Kaio Kitazato, Rudolf A Kley, Walter T Klimecki, Michael Klinkenberg, Jochen Klucken, Helene Knævelsrud, Erwin Knecht, Laura Knuppertz, Jiunn-Liang Ko, Satoru Kobayashi, Jan C Koch, Christelle Koechlin-Ramonatxo, Ulrich Koenig, Young Ho Koh, Katja Köhler, Sepp D Kohlwein, Masato Koike, Masaaki Komatsu, Eiki Kominami, Dexin Kong, Hee Jeong Kong, Eumorphia G Konstantakou, Benjamin T Kopp, Tamas Korcsmaros, Laura Korhonen, Viktor I Korolchuk, Nadya V Koshkina, Yanjun Kou, Michael I Koukourakis, Constantinos Koumenis, Attila L Kovács, Tibor Kovács, Werner J Kovacs, Daisuke Koya, Claudine Kraft, Dimitri Krainc, Helmut Kramer, Tamara Kravic-Stevovic, Wilhelm Krek, Carole Kretz-Remy, Roswitha Krick, Malathi Krishnamurthy, Janos Kriston-Vizi, Guido Kroemer, Michael C Kruer, Rejko Kruger, Nicholas T Ktistakis, Kazuyuki Kuchitsu, Christian Kuhn, Addanki Pratap Kumar, Anuj Kumar, Ashok Kumar, Deepak Kumar, Dhiraj Kumar, Rakesh Kumar, Sharad Kumar, Mondira Kundu, Hsing-Jien Kung, Atsushi Kuno, Sheng-Han Kuo, Jeff Kuret, Tino Kurz, Terry Kwok, Taeg Kyu Kwon, Yong Tae Kwon, Irene Kyrmizi, Albert R La Spada, Frank Lafont, Tim Lahm, Aparna Lakkaraju, Truong Lam, Trond Lamark, Steve Lancel, Terry H Landowski, Darius J R Lane, Jon D Lane, Cinzia Lanzi, Pierre Lapaquette, Louis R Lapierre, Jocelyn Laporte, Johanna Laukkarinen, Gordon W Laurie, Sergio Lavandero, Lena Lavie, Matthew J LaVoie, Betty Yuen Kwan Law, Helen Ka-Wai Law, Kelsey B Law, Robert Layfield, Pedro A Lazo, Laurent Le Cam, Karine G Le Roch, Hervé Le Stunff, Vijittra Leardkamolkarn, Marc Lecuit, Byung-Hoon Lee, Che-Hsin Lee, Erinna F Lee, Gyun Min Lee, He-Jin Lee, Hsinyu Lee, Jae Keun Lee, Jongdae Lee, Ju-Hyun Lee, Jun Hee Lee, Michael Lee, Myung-Shik Lee, Patty J Lee, Sam W Lee, Seung-Jae Lee, Shiow-Ju Lee, Stella Y Lee, Sug Hyung Lee, Sung Sik Lee, Sung-Joon Lee, Sunhee Lee, Ying-Ray Lee, Yong J Lee, Young H Lee, Christiaan Leeuwenburgh, Sylvain Lefort, Renaud Legouis, Jinzhi Lei, Qun-Ying Lei, David A Leib, Gil Leibowitz, Istvan Lekli, Stéphane D Lemaire, John J Lemasters, Marius K Lemberg, Antoinette Lemoine, Shuilong Leng, Guido Lenz, Paola Lenzi, Lilach O Lerman, Daniele Lettieri Barbato, Julia I-Ju Leu, Hing Y Leung, Beth Levine, Patrick A Lewis, Frank Lezoualc'h, Chi Li, Faqiang Li, Feng-Jun Li, Jun Li, Ke Li, Lian Li, Min Li, Min Li, Qiang Li, Rui Li, Sheng Li, Wei Li, Wei Li, Xiaotao Li, Yumin Li, Jiqin Lian, Chengyu Liang, Qiangrong Liang, Yulin Liao, Joana Liberal, Pawel P Liberski, Pearl Lie, Andrew P Lieberman, Hyunjung Jade Lim, Kah-Leong Lim, Kyu Lim, Raquel T Lima, Chang-Shen Lin, Chiou-Feng Lin, Fang Lin, Fangming Lin, Fu-Cheng Lin, Kui Lin, Kwang-Huei Lin, Pei-Hui Lin, Tianwei Lin, Wan-Wan Lin, Yee-Shin Lin, Yong Lin, Rafael Linden, Dan Lindholm, Lisa M Lindqvist, Paul Lingor, Andreas Linkermann, Lance A Liotta, Marta M Lipinski, Vitor A Lira, Michael P Lisanti, Paloma B Liton, Bo Liu, Chong Liu, Chun-Feng Liu, Fei Liu, Hung-Jen Liu, Jianxun Liu, Jing-Jing Liu, Jing-Lan Liu, Ke Liu, Leyuan Liu, Liang Liu, Quentin Liu, Rong-Yu Liu, Shiming Liu, Shuwen Liu, Wei Liu, Xian-De Liu, Xiangguo Liu, Xiao-Hong Liu, Xinfeng Liu, Xu Liu, Xueqin Liu, Yang Liu, Yule Liu, Zexian Liu, Zhe Liu, Juan P Liuzzi, Gérard Lizard, Mila Ljujic, Irfan J Lodhi, Susan E Logue, Bal L Lokeshwar, Yun Chau Long, Sagar Lonial, Benjamin Loos, Carlos López-Otín, Cristina López-Vicario, Mar Lorente, Philip L Lorenzi, Péter Lõrincz, Marek Los, Michael T Lotze, Penny E Lovat, Binfeng Lu, Bo Lu, Jiahong Lu, Qing Lu, She-Min Lu, Shuyan Lu, Yingying Lu, Frédéric Luciano, Shirley Luckhart, John Milton Lucocq, Paula Ludovico, Aurelia Lugea, Nicholas W Lukacs, Julian J Lum, Anders H Lund, Honglin Luo, Jia Luo, Shouqing Luo, Claudio Luparello, Timothy Lyons, Jianjie Ma, Yi Ma, Yong Ma, Zhenyi Ma, Juliano Machado, Glaucia M Machado-Santelli, Fernando Macian, Gustavo C MacIntosh, Jeffrey P MacKeigan, Kay F Macleod, John D MacMicking, Lee Ann MacMillan-Crow, Frank Madeo, Muniswamy Madesh, Julio Madrigal-Matute, Akiko Maeda, Tatsuya Maeda, Gustavo Maegawa, Emilia Maellaro, Hannelore Maes, Marta Magariños, Kenneth Maiese, Tapas K Maiti, Luigi Maiuri, Maria Chiara Maiuri, Carl G Maki, Roland Malli, Walter Malorni, Alina Maloyan, Fathia Mami-Chouaib, Na Man, Joseph D Mancias, Eva-Maria Mandelkow, Michael A Mandell, Angelo A Manfredi, Serge N Manié, Claudia Manzoni, Kai Mao, Zixu Mao, Zong-Wan Mao, Philippe Marambaud, Anna Maria Marconi, Zvonimir Marelja, Gabriella Marfe, Marta Margeta, Eva Margittai, Muriel Mari, Francesca V Mariani, Concepcio Marin, Sara Marinelli, Guillermo Mariño, Ivanka Markovic, Rebecca Marquez, Alberto M Martelli, Sascha Martens, Katie R Martin, Seamus J Martin, Shaun Martin, Miguel A Martin-Acebes, Paloma Martín-Sanz, Camille Martinand-Mari, Wim Martinet, Jennifer Martinez, Nuria Martinez-Lopez, Ubaldo Martinez-Outschoorn, Moisés Martínez-Velázquez, Marta Martinez-Vicente, Waleska Kerllen Martins, Hirosato Mashima, James A Mastrianni, Giuseppe Matarese, Paola Matarrese, Roberto Mateo, Satoaki Matoba, Naomichi Matsumoto, Takehiko Matsushita, Akira Matsuura, Takeshi Matsuzawa, Mark P Mattson, Soledad Matus, Norma Maugeri, Caroline Mauvezin, Andreas Mayer, Dusica Maysinger, Guillermo D Mazzolini, Mary Kate McBrayer, Kimberly McCall, Craig McCormick, Gerald M McInerney, Skye C McIver, Sharon McKenna, John J McMahon, Iain A McNeish, Fatima Mechta-Grigoriou, Jan Paul Medema, Diego L Medina, Klara Megyeri, Maryam Mehrpour, Jawahar L Mehta, Yide Mei, Ute-Christiane Meier, Alfred J Meijer, Alicia Meléndez, Gerry Melino, Sonia Melino, Edesio Jose Tenorio de Melo, Maria A Mena, Marc D Meneghini, Javier A Menendez, Regina Menezes, Liesu Meng, Ling-Hua Meng, Songshu Meng, Rossella Menghini, A Sue Menko, Rubem Fs Menna-Barreto, Manoj B Menon, Marco A Meraz-Ríos, Giuseppe Merla, Luciano Merlini, Angelica M Merlot, Andreas Meryk, Stefania Meschini, Joel N Meyer, Man-Tian Mi, Chao-Yu Miao, Lucia Micale, Simon Michaeli, Carine Michiels, Anna Rita Migliaccio, Anastasia Susie Mihailidou, Dalibor Mijaljica, Katsuhiko Mikoshiba, Enrico Milan, Leonor Miller-Fleming, Gordon B Mills, Ian G Mills, Georgia Minakaki, Berge A Minassian, Xiu-Fen Ming, Farida Minibayeva, Elena A Minina, Justine D Mintern, Saverio Minucci, Antonio Miranda-Vizuete, Claire H Mitchell, Shigeki Miyamoto, Keisuke Miyazawa, Noboru Mizushima, Katarzyna Mnich, Baharia Mograbi, Simin Mohseni, Luis Ferreira Moita, Marco Molinari, Maurizio Molinari, Andreas Buch Møller, Bertrand Mollereau, Faustino Mollinedo, Marco Mongillo, Martha M Monick, Serena Montagnaro, Craig Montell, Darren J Moore, Michael N Moore, Rodrigo Mora-Rodriguez, Paula I Moreira, Etienne Morel, Maria Beatrice Morelli, Sandra Moreno, Michael J Morgan, Arnaud Moris, Yuji Moriyasu, Janna L Morrison, Lynda A Morrison, Eugenia Morselli, Jorge Moscat, Pope L Moseley, Serge Mostowy, Elisa Motori, Denis Mottet, Jeremy C Mottram, Charbel E-H Moussa, Vassiliki E Mpakou, Hasan Mukhtar, Jean M Mulcahy Levy, Sylviane Muller, Raquel Muñoz-Moreno, Cristina Muñoz-Pinedo, Christian Münz, Maureen E Murphy, James T Murray, Aditya Murthy, Indira U Mysorekar, Ivan R Nabi, Massimo Nabissi, Gustavo A Nader, Yukitoshi Nagahara, Yoshitaka Nagai, Kazuhiro Nagata, Anika Nagelkerke, Péter Nagy, Samisubbu R Naidu, Sreejayan Nair, Hiroyasu Nakano, Hitoshi Nakatogawa, Meera Nanjundan, Gennaro Napolitano, Naweed I Naqvi, Roberta Nardacci, Derek P Narendra, Masashi Narita, Anna Chiara Nascimbeni, Ramesh Natarajan, Luiz C Navegantes, Steffan T Nawrocki, Taras Y Nazarko, Volodymyr Y Nazarko, Thomas Neill, Luca M Neri, Mihai G Netea, Romana T Netea-Maier, Bruno M Neves, Paul A Ney, Ioannis P Nezis, Hang Tt Nguyen, Huu Phuc Nguyen, Anne-Sophie Nicot, Hilde Nilsen, Per Nilsson, Mikio Nishimura, Ichizo Nishino, Mireia Niso-Santano, Hua Niu, Ralph A Nixon, Vincent Co Njar, Takeshi Noda, Angelika A Noegel, Elsie Magdalena Nolte, Erik Norberg, Koenraad K Norga, Sakineh Kazemi Noureini, Shoji Notomi, Lucia Notterpek, Karin Nowikovsky, Nobuyuki Nukina, Thorsten Nürnberger, Valerie B O'Donnell, Tracey O'Donovan, Peter J O'Dwyer, Ina Oehme, Clara L Oeste, Michinaga Ogawa, Besim Ogretmen, Yuji Ogura, Young J Oh, Masaki Ohmuraya, Takayuki Ohshima, Rani Ojha, Koji Okamoto, Toshiro Okazaki, F Javier Oliver, Karin Ollinger, Stefan Olsson, Daniel P Orban, Paulina Ordonez, Idil Orhon, Laszlo Orosz, Eyleen J O'Rourke, Helena Orozco, Angel L Ortega, Elena Ortona, Laura D Osellame, Junko Oshima, Shigeru Oshima, Heinz D Osiewacz, Takanobu Otomo, Kinya Otsu, Jing-Hsiung James Ou, Tiago F Outeiro, Dong-Yun Ouyang, Hongjiao Ouyang, Michael Overholtzer, Michelle A Ozbun, P Hande Ozdinler, Bulent Ozpolat, Consiglia Pacelli, Paolo Paganetti, Guylène Page, Gilles Pages, Ugo Pagnini, Beata Pajak, Stephen C Pak, Karolina Pakos-Zebrucka, Nazzy Pakpour, Zdena Palková, Francesca Palladino, Kathrin Pallauf, Nicolas Pallet, Marta Palmieri, Søren R Paludan, Camilla Palumbo, Silvia Palumbo, Olatz Pampliega, Hongming Pan, Wei Pan, Theocharis Panaretakis, Aseem Pandey, Areti Pantazopoulou, Zuzana Papackova, Daniela L Papademetrio, Issidora Papassideri, Alessio Papini, Nirmala Parajuli, Julian Pardo, Vrajesh V Parekh, Giancarlo Parenti, Jong-In Park, Junsoo Park, Ohkmae K Park, Roy Parker, Rosanna Parlato, Jan B Parys, Katherine R Parzych, Jean-Max Pasquet, Benoit Pasquier, Kishore Bs Pasumarthi, Daniel Patschan, Cam Patterson, Sophie Pattingre, Scott Pattison, Arnim Pause, Hermann Pavenstädt, Flaminia Pavone, Zully Pedrozo, Fernando J Peña, Miguel A Peñalva, Mario Pende, Jianxin Peng, Fabio Penna, Josef M Penninger, Anna Pensalfini, Salvatore Pepe, Gustavo Js Pereira, Paulo C Pereira, Verónica Pérez-de la Cruz, María Esther Pérez-Pérez, Diego Pérez-Rodríguez, Dolores Pérez-Sala, Celine Perier, Andras Perl, David H Perlmutter, Ida Perrotta, Shazib Pervaiz, Maija Pesonen, Jeffrey E Pessin, Godefridus J Peters, Morten Petersen, Irina Petrache, Basil J Petrof, Goran Petrovski, James M Phang, Mauro Piacentini, Marina Pierdominici, Philippe Pierre, Valérie Pierrefite-Carle, Federico Pietrocola, Felipe X Pimentel-Muiños, Mario Pinar, Benjamin Pineda, Ronit Pinkas-Kramarski, Marcello Pinti, Paolo Pinton, Bilal Piperdi, James M Piret, Leonidas C Platanias, Harald W Platta, Edward D Plowey, Stefanie Pöggeler, Marc Poirot, Peter Polčic, Angelo Poletti, Audrey H Poon, Hana Popelka, Blagovesta Popova, Izabela Poprawa, Shibu M Poulose, Joanna Poulton, Scott K Powers, Ted Powers, Mercedes Pozuelo-Rubio, Krisna Prak, Reinhild Prange, Mark Prescott, Muriel Priault, Sharon Prince, Richard L Proia, Tassula Proikas-Cezanne, Holger Prokisch, Vasilis J Promponas, Karin Przyklenk, Rosa Puertollano, Subbiah Pugazhenthi, Luigi Puglielli, Aurora Pujol, Julien Puyal, Dohun Pyeon, Xin Qi, Wen-Bin Qian, Zheng-Hong Qin, Yu Qiu, Ziwei Qu, Joe Quadrilatero, Frederick Quinn, Nina Raben, Hannah Rabinowich, Flavia Radogna, Michael J Ragusa, Mohamed Rahmani, Komal Raina, Sasanka Ramanadham, Rajagopal Ramesh, Abdelhaq Rami, Sarron Randall-Demllo, Felix Randow, Hai Rao, V Ashutosh Rao, Blake B Rasmussen, Tobias M Rasse, Edward A Ratovitski, Pierre-Emmanuel Rautou, Swapan K Ray, Babak Razani, Bruce H Reed, Fulvio Reggiori, Markus Rehm, Andreas S Reichert, Theo Rein, David J Reiner, Eric Reits, Jun Ren, Xingcong Ren, Maurizio Renna, Jane Eb Reusch, Jose L Revuelta, Leticia Reyes, Alireza R Rezaie, Robert I Richards, Des R Richardson, Clémence Richetta, Michael A Riehle, Bertrand H Rihn, Yasuko Rikihisa, Brigit E Riley, Gerald Rimbach, Maria Rita Rippo, Konstantinos Ritis, Federica Rizzi, Elizete Rizzo, Peter J Roach, Jeffrey Robbins, Michel Roberge, Gabriela Roca, Maria Carmela Roccheri, Sonia Rocha, Cecilia Mp Rodrigues, Clara I Rodríguez, Santiago Rodriguez de Cordoba, Natalia Rodriguez-Muela, Jeroen Roelofs, Vladimir V Rogov, Troy T Rohn, Bärbel Rohrer, Davide Romanelli, Luigina Romani, Patricia Silvia Romano, M Isabel G Roncero, Jose Luis Rosa, Alicia Rosello, Kirill V Rosen, Philip Rosenstiel, Magdalena Rost-Roszkowska, Kevin A Roth, Gael Roué, Mustapha Rouis, Kasper M Rouschop, Daniel T Ruan, Diego Ruano, David C Rubinsztein, Edmund B Rucker 3rd, Assaf Rudich, Emil Rudolf, Ruediger Rudolf, Markus A Ruegg, Carmen Ruiz-Roldan, Avnika Ashok Ruparelia, Paola Rusmini, David W Russ, Gian Luigi Russo, Giuseppe Russo, Rossella Russo, Tor Erik Rusten, Victoria Ryabovol, Kevin M Ryan, Stefan W Ryter, David M Sabatini, Michael Sacher, Carsten Sachse, Michael N Sack, Junichi Sadoshima, Paul Saftig, Ronit Sagi-Eisenberg, Sumit Sahni, Pothana Saikumar, Tsunenori Saito, Tatsuya Saitoh, Koichi Sakakura, Machiko Sakoh-Nakatogawa, Yasuhito Sakuraba, María Salazar-Roa, Paolo Salomoni, Ashok K Saluja, Paul M Salvaterra, Rosa Salvioli, Afshin Samali, Anthony Mj Sanchez, José A Sánchez-Alcázar, Ricardo Sanchez-Prieto, Marco Sandri, Miguel A Sanjuan, Stefano Santaguida, Laura Santambrogio, Giorgio Santoni, Claudia Nunes Dos Santos, Shweta Saran, Marco Sardiello, Graeme Sargent, Pallabi Sarkar, Sovan Sarkar, Maria Rosa Sarrias, Minnie M Sarwal, Chihiro Sasakawa, Motoko Sasaki, Miklos Sass, Ken Sato, Miyuki Sato, Joseph Satriano, Niramol Savaraj, Svetlana Saveljeva, Liliana Schaefer, Ulrich E Schaible, Michael Scharl, Hermann M Schatzl, Randy Schekman, Wiep Scheper, Alfonso Schiavi, Hyman M Schipper, Hana Schmeisser, Jens Schmidt, Ingo Schmitz, Bianca E Schneider, E Marion Schneider, Jaime L Schneider, Eric A Schon, Miriam J Schönenberger, Axel H Schönthal, Daniel F Schorderet, Bernd Schröder, Sebastian Schuck, Ryan J Schulze, Melanie Schwarten, Thomas L Schwarz, Sebastiano Sciarretta, Kathleen Scotto, A Ivana Scovassi, Robert A Screaton, Mark Screen, Hugo Seca, Simon Sedej, Laura Segatori, Nava Segev, Per O Seglen, Jose M Seguí-Simarro, Juan Segura-Aguilar, Ekihiro Seki, Christian Sell, Iban Seiliez, Clay F Semenkovich, Gregg L Semenza, Utpal Sen, Andreas L Serra, Ana Serrano-Puebla, Hiromi Sesaki, Takao Setoguchi, Carmine Settembre, John J Shacka, Ayesha N Shajahan-Haq, Irving M Shapiro, Shweta Sharma, Hua She, C-K James Shen, Chiung-Chyi Shen, Han-Ming Shen, Sanbing Shen, Weili Shen, Rui Sheng, Xianyong Sheng, Zu-Hang Sheng, Trevor G Shepherd, Junyan Shi, Qiang Shi, Qinghua Shi, Yuguang Shi, Shusaku Shibutani, Kenichi Shibuya, Yoshihiro Shidoji, Jeng-Jer Shieh, Chwen-Ming Shih, Yohta Shimada, Shigeomi Shimizu, Dong Wook Shin, Mari L Shinohara, Michiko Shintani, Takahiro Shintani, Tetsuo Shioi, Ken Shirabe, Ronit Shiri-Sverdlov, Orian Shirihai, Gordon C Shore, Chih-Wen Shu, Deepak Shukla, Andriy A Sibirny, Valentina Sica, Christina J Sigurdson, Einar M Sigurdsson, Puran Singh Sijwali, Beata Sikorska, Wilian A Silveira, Sandrine Silvente-Poirot, Gary A Silverman, Jan Simak, Thomas Simmet, Anna Katharina Simon, Hans-Uwe Simon, Cristiano Simone, Matias Simons, Anne Simonsen, Rajat Singh, Shivendra V Singh, Shrawan K Singh, Debasish Sinha, Sangita Sinha, Frank A Sinicrope, Agnieszka Sirko, Kapil Sirohi, Balindiwe Jn Sishi, Annie Sittler, Parco M Siu, Efthimios Sivridis, Anna Skwarska, Ruth Slack, Iva Slaninová, Nikolai Slavov, Soraya S Smaili, Keiran Sm Smalley, Duncan R Smith, Stefaan J Soenen, Scott A Soleimanpour, Anita Solhaug, Kumaravel Somasundaram, Jin H Son, Avinash Sonawane, Chunjuan Song, Fuyong Song, Hyun Kyu Song, Ju-Xian Song, Wei Song, Kai Y Soo, Anil K Sood, Tuck Wah Soong, Virawudh Soontornniyomkij, Maurizio Sorice, Federica Sotgia, David R Soto-Pantoja, Areechun Sotthibundhu, Maria João Sousa, Herman P Spaink, Paul N Span, Anne Spang, Janet D Sparks, Peter G Speck, Stephen A Spector, Claudia D Spies, Wolfdieter Springer, Daret St Clair, Alessandra Stacchiotti, Bart Staels, Michael T Stang, Daniel T Starczynowski, Petro Starokadomskyy, Clemens Steegborn, John W Steele, Leonidas Stefanis, Joan Steffan, Christine M Stellrecht, Harald Stenmark, Tomasz M Stepkowski, Stęphan T Stern, Craig Stevens, Brent R Stockwell, Veronika Stoka, Zuzana Storchova, Björn Stork, Vassilis Stratoulias, Dimitrios J Stravopodis, Pavel Strnad, Anne Marie Strohecker, Anna-Lena Ström, Per Stromhaug, Jiri Stulik, Yu-Xiong Su, Zhaoliang Su, Carlos S Subauste, Srinivasa Subramaniam, Carolyn M Sue, Sang Won Suh, Xinbing Sui, Supawadee Sukseree, David Sulzer, Fang-Lin Sun, Jiaren Sun, Jun Sun, Shi-Yong Sun, Yang Sun, Yi Sun, Yingjie Sun, Vinod Sundaramoorthy, Joseph Sung, Hidekazu Suzuki, Kuninori Suzuki, Naoki Suzuki, Tadashi Suzuki, Yuichiro J Suzuki, Michele S Swanson, Charles Swanton, Karl Swärd, Ghanshyam Swarup, Sean T Sweeney, Paul W Sylvester, Zsuzsanna Szatmari, Eva Szegezdi, Peter W Szlosarek, Heinrich Taegtmeyer, Marco Tafani, Emmanuel Taillebourg, Stephen Wg Tait, Krisztina Takacs-Vellai, Yoshinori Takahashi, Szabolcs Takáts, Genzou Takemura, Nagio Takigawa, Nicholas J Talbot, Elena Tamagno, Jerome Tamburini, Cai-Ping Tan, Lan Tan, Mei Lan Tan, Ming Tan, Yee-Joo Tan, Keiji Tanaka, Masaki Tanaka, Daolin Tang, Dingzhong Tang, Guomei Tang, Isei Tanida, Kunikazu Tanji, Bakhos A Tannous, Jose A Tapia, Inmaculada Tasset-Cuevas, Marc Tatar, Iman Tavassoly, Nektarios Tavernarakis, Allen Taylor, Graham S Taylor, Gregory A Taylor, J Paul Taylor, Mark J Taylor, Elena V Tchetina, Andrew R Tee, Fatima Teixeira-Clerc, Sucheta Telang, Tewin Tencomnao, Ba-Bie Teng, Ru-Jeng Teng, Faraj Terro, Gianluca Tettamanti, Arianne L Theiss, Anne E Theron, Kelly Jean Thomas, Marcos P Thomé, Paul G Thomes, Andrew Thorburn, Jeremy Thorner, Thomas Thum, Michael Thumm, Teresa Lm Thurston, Ling Tian, Andreas Till, Jenny Pan-Yun Ting, Vladimir I Titorenko, Lilach Toker, Stefano Toldo, Sharon A Tooze, Ivan Topisirovic, Maria Lyngaas Torgersen, Liliana Torosantucci, Alicia Torriglia, Maria Rosaria Torrisi, Cathy Tournier, Roberto Towns, Vladimir Trajkovic, Leonardo H Travassos, Gemma Triola, Durga Nand Tripathi, Daniela Trisciuoglio, Rodrigo Troncoso, Ioannis P Trougakos, Anita C Truttmann, Kuen-Jer Tsai, Mario P Tschan, Yi-Hsin Tseng, Takayuki Tsukuba, Allan Tsung, Andrey S Tsvetkov, Shuiping Tu, Hsing-Yu Tuan, Marco Tucci, David A Tumbarello, Boris Turk, Vito Turk, Robin Fb Turner, Anders A Tveita, Suresh C Tyagi, Makoto Ubukata, Yasuo Uchiyama, Andrej Udelnow, Takashi Ueno, Midori Umekawa, Rika Umemiya-Shirafuji, Benjamin R Underwood, Christian Ungermann, Rodrigo P Ureshino, Ryo Ushioda, Vladimir N Uversky, Néstor L Uzcátegui, Thomas Vaccari, Maria I Vaccaro, Libuše Váchová, Helin Vakifahmetoglu-Norberg, Rut Valdor, Enza Maria Valente, Francois Vallette, Angela M Valverde, Greet Van den Berghe, Ludo Van Den Bosch, Gijs R van den Brink, F Gisou van der Goot, Ida J van der Klei, Luc Jw van der Laan, Wouter G van Doorn, Marjolein van Egmond, Kenneth L van Golen, Luc Van Kaer, Menno van Lookeren Campagne, Peter Vandenabeele, Wim Vandenberghe, Ilse Vanhorebeek, Isabel Varela-Nieto, M Helena Vasconcelos, Radovan Vasko, Demetrios G Vavvas, Ignacio Vega-Naredo, Guillermo Velasco, Athanassios D Velentzas, Panagiotis D Velentzas, Tibor Vellai, Edo Vellenga, Mikkel Holm Vendelbo, Kartik Venkatachalam, Natascia Ventura, Salvador Ventura, Patrícia St Veras, Mireille Verdier, Beata G Vertessy, Andrea Viale, Michel Vidal, Helena L A Vieira, Richard D Vierstra, Nadarajah Vigneswaran, Neeraj Vij, Miquel Vila, Margarita Villar, Victor H Villar, Joan Villarroya, Cécile Vindis, Giampietro Viola, Maria Teresa Viscomi, Giovanni Vitale, Dan T Vogl, Olga V Voitsekhovskaja, Clarissa von Haefen, Karin von Schwarzenberg, Daniel E Voth, Valérie Vouret-Craviari, Kristina Vuori, Jatin M Vyas, Christian Waeber, Cheryl Lyn Walker, Mark J Walker, Jochen Walter, Lei Wan, Xiangbo Wan, Bo Wang, Caihong Wang, Chao-Yung Wang, Chengshu Wang, Chenran Wang, Chuangui Wang, Dong Wang, Fen Wang, Fuxin Wang, Guanghui Wang, Hai-Jie Wang, Haichao Wang, Hong-Gang Wang, Hongmin Wang, Horng-Dar Wang, Jing Wang, Junjun Wang, Mei Wang, Mei-Qing Wang, Pei-Yu Wang, Peng Wang, Richard C Wang, Shuo Wang, Ting-Fang Wang, Xian Wang, Xiao-Jia Wang, Xiao-Wei Wang, Xin Wang, Xuejun Wang, Yan Wang, Yanming Wang, Ying Wang, Ying-Jan Wang, Yipeng Wang, Yu Wang, Yu Tian Wang, Yuqing Wang, Zhi-Nong Wang, Pablo Wappner, Carl Ward, Diane McVey Ward, Gary Warnes, Hirotaka Watada, Yoshihisa Watanabe, Kei Watase, Timothy E Weaver, Colin D Weekes, Jiwu Wei, Thomas Weide, Conrad C Weihl, Günther Weindl, Simone Nardin Weis, Longping Wen, Xin Wen, Yunfei Wen, Benedikt Westermann, Cornelia M Weyand, Anthony R White, Eileen White, J Lindsay Whitton, Alexander J Whitworth, Joëlle Wiels, Franziska Wild, Manon E Wildenberg, Tom Wileman, Deepti Srinivas Wilkinson, Simon Wilkinson, Dieter Willbold, Chris Williams, Katherine Williams, Peter R Williamson, Konstanze F Winklhofer, Steven S Witkin, Stephanie E Wohlgemuth, Thomas Wollert, Ernst J Wolvetang, Esther Wong, G William Wong, Richard W Wong, Vincent Kam Wai Wong, Elizabeth A Woodcock, Karen L Wright, Chunlai Wu, Defeng Wu, Gen Sheng Wu, Jian Wu, Junfang Wu, Mian Wu, Min Wu, Shengzhou Wu, William Kk Wu, Yaohua Wu, Zhenlong Wu, Cristina Pr Xavier, Ramnik J Xavier, Gui-Xian Xia, Tian Xia, Weiliang Xia, Yong Xia, Hengyi Xiao, Jian Xiao, Shi Xiao, Wuhan Xiao, Chuan-Ming Xie, Zhiping Xie, Zhonglin Xie, Maria Xilouri, Yuyan Xiong, Chuanshan Xu, Congfeng Xu, Feng Xu, Haoxing Xu, Hongwei Xu, Jian Xu, Jianzhen Xu, Jinxian Xu, Liang Xu, Xiaolei Xu, Yangqing Xu, Ye Xu, Zhi-Xiang Xu, Ziheng Xu, Yu Xue, Takahiro Yamada, Ai Yamamoto, Koji Yamanaka, Shunhei Yamashina, Shigeko Yamashiro, Bing Yan, Bo Yan, Xianghua Yan, Zhen Yan, Yasuo Yanagi, Dun-Sheng Yang, Jin-Ming Yang, Liu Yang, Minghua Yang, Pei-Ming Yang, Peixin Yang, Qian Yang, Wannian Yang, Wei Yuan Yang, Xuesong Yang, Yi Yang, Ying Yang, Zhifen Yang, Zhihong Yang, Meng-Chao Yao, Pamela J Yao, Xiaofeng Yao, Zhenyu Yao, Zhiyuan Yao, Linda S Yasui, Mingxiang Ye, Barry Yedvobnick, Behzad Yeganeh, Elizabeth S Yeh, Patricia L Yeyati, Fan Yi, Long Yi, Xiao-Ming Yin, Calvin K Yip, Yeong-Min Yoo, Young Hyun Yoo, Seung-Yong Yoon, Ken-Ichi Yoshida, Tamotsu Yoshimori, Ken H Young, Huixin Yu, Jane J Yu, Jin-Tai Yu, Jun Yu, Li Yu, W Haung Yu, Xiao-Fang Yu, Zhengping Yu, Junying Yuan, Zhi-Min Yuan, Beatrice Yjt Yue, Jianbo Yue, Zhenyu Yue, David N Zacks, Eldad Zacksenhaus, Nadia Zaffaroni, Tania Zaglia, Zahra Zakeri, Vincent Zecchini, Jinsheng Zeng, Min Zeng, Qi Zeng, Antonis S Zervos, Donna D Zhang, Fan Zhang, Guo Zhang, Guo-Chang Zhang, Hao Zhang, Hong Zhang, Hong Zhang, Hongbing Zhang, Jian Zhang, Jian Zhang, Jiangwei Zhang, Jianhua Zhang, Jing-Pu Zhang, Li Zhang, Lin Zhang, Lin Zhang, Long Zhang, Ming-Yong Zhang, Xiangnan Zhang, Xu Dong Zhang, Yan Zhang, Yang Zhang, Yanjin Zhang, Yingmei Zhang, Yunjiao Zhang, Mei Zhao, Wei-Li Zhao, Xiaonan Zhao, Yan G Zhao, Ying Zhao, Yongchao Zhao, Yu-Xia Zhao, Zhendong Zhao, Zhizhuang J Zhao, Dexian Zheng, Xi-Long Zheng, Xiaoxiang Zheng, Boris Zhivotovsky, Qing Zhong, Guang-Zhou Zhou, Guofei Zhou, Huiping Zhou, Shu-Feng Zhou, Xu-Jie Zhou, Hongxin Zhu, Hua Zhu, Wei-Guo Zhu, Wenhua Zhu, Xiao-Feng Zhu, Yuhua Zhu, Shi-Mei Zhuang, Xiaohong Zhuang, Elio Ziparo, Christos E Zois, Teresa Zoladek, Wei-Xing Zong, Antonio Zorzano, Susu M Zughaier Autophagy 12 (1) 1 -222 2016年 [査読有り][通常論文]

共同研究・競争的資金等の研究課題

  • オートファジーに立脚した急性膵炎発症・進展の分子機構の解析
    文部科学省:科学研究費補助金 基盤研究(C)
    研究期間 : 2016年04月 -2019年03月 
    代表者 : 大西 洋英
  • 急性膵炎におけるカルシウム結合蛋白の役割―新たな創薬を目指して
    文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2016年04月 -2019年03月 
    代表者 : 眞嶋 浩聡
  • 文部科学省:科学研究費補助金(挑戦的萌芽研究)
    研究期間 : 2013年 -2015年 
    代表者 : 大西 洋英, 真嶋 浩聡, 堀江 泰夫, 三浦 光一
     
    急性膵炎の発症、進展には膵腺房細胞におけるオートファジーが深く関与していることが推測されている。一方、本研究対象であるSNARE蛋白ファミリーの中でもVAMP7蛋白はオートファジー機構の中でオートファゴゾームの形成の初期段階に不可欠な蛋白とされている。本研究において我々はまず最初に膵腺房細胞にVAKP7が発現している事を確認した。そして、急性膵炎の発症、進展におけるVAMP7の機能を検討すべく、VAMP7-FLOXマウスと膵臓腺房細胞特異的に発現するSPINK-3遺伝子のpromoterによりCre-recombinase を発現するSpink3-Creマウスを交配することにより、膵腺房細胞特異的VAMP7遺伝子欠損マウスを作製した。膵腺房細胞特異的VAMP7遺伝子欠損マウスにおける膵臓は、マクロならびにミクロの形態学的解析においては、コントロールマウスと比べても明らかな変化は認めなかった。一方、この膵腺房細胞特異的VAMP7遺伝子欠損マウスに対して、腹腔内にセルレイン投与いよる急性膵炎を惹起したところ、その膵炎の炎症程度はコントロールマウスに比べて著明に増悪していることが、病理学的検索にて認められた。更にその原因を調べるべく急性膵炎を惹起した本KOマウスとコントロールマウスの膵腺房細胞内のトリプシン活性を比較検討したところ、KOマウスの膵腺房細胞内のトリプシン活性がコントロールマウスに比べて急性膵炎惹起早期より著明に上昇していることを確認した。このことより、本KOマウスにおけるセルレイン惹起性急性膵炎の炎症増悪現象の一因にはトリプシン活性の上昇が考えられた。現在は、KOマウスにおけるセルレイン惹起性急性膵炎にみ止められたトリプシン活性の上昇とVAMP7遺伝子欠損によるオートファジー機構変化との関連を検討している。
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2012年 -2014年 
    代表者 : 真嶋 浩聡, 大西 洋英
     
    昨年度までの検討で急性膵炎発症に関わる蛋白を絞り込み、S100ファミリー、アネキシンファミリーに属する2種類のカルシウム結合蛋白質が急性膵炎の発症と重要な関連を持っていることを明らかにした。これらの因子と急性膵炎との関連を詳細に検討するために、国際ノックアウトマウスコンソーシアムよりES細胞を購入し、ノックアウトマウスの作成を試みた。しかし、キメラマウスは作成できたものの、そこからヘテロマウスを作成することができなかった。つまり、変異が生殖細胞にまで反映されておらず、これは他のプロジェクトの進行とも照らしあわせるとES細胞の不良が考えられた。文献を検索するとS100ファミリー蛋白のノックアウトマウスはウィスコンシン大学、忠北大学校(韓国)が保有していた。ウィスコンシン大学のマウス杯はトラブルにより利用不可能となっていたが、韓国のグループとは共同研究が可能で、2014.6月にノックアウトマウスが届く予定となっている。届き次第に解析に移行する。野生型マウスに実験的膵炎を惹起し、急性膵炎反応の前後でS100ファミリー、アネキシンファミリーの蛋白の変化を免疫組織化学を用いて検討した。予想通り、急性膵炎の発症に伴い、これらの蛋白は早期に発現レベルが上昇し、膵炎発症との密接な関連が示唆された。細胞レベルでどのような機能をはたしているかを明らかにするために、ラット膵腺房細胞由来のAR42J細胞にレトロウイルスを用いて遺伝子変異を起こさせ、①コントロール細胞、②S100ファミリー蛋白過剰発現細胞、③アネキシンファミリー蛋白過剰発現細胞を樹立した。今後これらの細胞の性質の変化、カルシウムシグナルに及ぼす影響、膵炎反応時の挙動等を検討してゆく。
  • exocrine pancreas disorder
    Basic Research Promotion Service for Health and Medical Field
    研究期間 : 2009年 -2011年
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2009年 -2011年 
    代表者 : 真嶋 浩聡, 大西 洋英
     
    Irf2^<-/->マウスに見られる膵臓の異常は、調節性外分泌の障害が原因であった。その結果、酵素顆粒が細胞内に充満し、軽度の膵炎が進行していた。しかし、IRF2は酵素顆粒と細胞膜の結合・癒合に関わるSNARE蛋白質を直接的には制御しておらず、急性膵炎発症のメカニズムの解明のために、IRF2の標的分子の同定、分子メカニズムの解明が重要である。
  • 膵外分泌異常の解明
    研究期間 : 2008年 -2011年
  • 胃、大腸に特異的に発現する遺伝子の機能解析
    研究期間 : 2007年 -2011年
  • 膵臓の分化
    研究期間 : 2006年 -2010年
  • 文部科学省:科学研究費補助金(基盤研究(C))
    研究期間 : 2005年 -2007年 
    代表者 : 真嶋 浩聡
     
    膵外分泌腺由来AR42J細胞は共通前駆細胞の性質を持ち、アクチビンA+ベータセルリンの作用でインスリン産生細胞へ分化する。この時、多くの遺伝子の発現が変化する(Mashima, et. al.Diabetes48;304-9:1999)が、今回、Junctional Adhesion Molecule-1(JAM-1)に着目した。AR42J細胞がインスリン産生細胞へ分化する時、タイトジャンクション(TJ)を形成しないにも関わらず、TJの構成蛋白であるJAM-1は著明に発現が亢進する。JAM-1のAR42J細胞の分化に及ぼす影響の検討が本研究の主眼である。JAM-1はアクチビンA+ベータセルリンの添加後、mRNAレベルでは3時間後、蛋白レベルでは24時間後に発現の増加がみられた。TJからのシグナル伝達分子であるPAR-3やatypical PKCλも同様に発現が亢進した。AR42J細胞に過剰発現をさせると細胞表面だけでなく、細胞内小胞にも発現が認められた。TJの蛋白は細胞間接合部にとどまるのではなく、分裂や増殖にあわせて細胞内をリサイクリングしていることが最近明らかにされ、RabファミリーのRab3BやRab13が関与していると報告された。二重染色を行った所、JAM-1もやはり、Rab3BやRab13と同じ細胞内小胞に存在した。ストレプトゾトシンを腹腔内投与して糖尿病ラットを作成し、膵ラ氏島のJAM-1の発現を比較したところ、糖尿病ラットではJAM-1の発現が亢進していた。以上から、JAM-1はAR42J細胞のインスリン産生細胞への分化及び膵内分泌細胞の再生に重要な役割を果たしていることが明らかにされ、今後は胎生期の膵ラ氏島やJAM-1の発現変化がAR42J細胞の分化に及ぼす影響等を詳細に検討することにより、JAM-1の機能を明らかにしてゆく。
  • 文部科学省:科学研究費補助金(特定領域研究)
    研究期間 : 2004年 -2005年 
    代表者 : 平山 壽哉, 真嶋 浩聡
     
    ヘリコパクター・ピロリの持続感染は慢性胃炎、消化性漬瘍さらには胃癌や.MALTリンパ腫を引き起こすことガ知られている。ヘリコパクター・ピロリは胃粘膜に生息するが、胃粘膜細胞への侵入性はなく、強力な蛋白毒素である空胞化毒素、VacA毒素を産生する。本研究では、VacA毒素の胃粘膜障害にいたる細胞内シグナル伝達の流れを明らかにすることを目的とし、1)受容体の毒素結合部位と細胞内移行の機序、2)VacA毒素による細胞死の機構の二つに焦点を当てて解析した。その結果1)胃粘膜細胞のVacA毒素受容体であるRPTPβのN末端より数えて747-751番目のアミノ嘩(QQP)がVacA毒素結合に必須であり、加えて748位あるいは789位のThrが結合に重要であることが判明した。747-751番目のアミノ酸(QTTQP)はO-glycosylationされていることが示唆されており、VacA毒素との結合にシアル酸が重要であることとも一致した。一方、VacA毒素の細胞内移行にはlipid raftの関与が重要であることが知られていたが、RPTPβの関与については明らかにされていない。我々は、VacA毒素が最初にlipid raft以外の細胞膜上に存在するRPTPβに結合し、その後温度依存的にlipid raftに集積し、その後に細胞内へ移行することを明らかにした。さらに空胞形成及びp38MAPキナーゼの活性化には細胞膜にあるGPI-anchored proteinが必須であることが分かった(投稿中)。2)VacA毒素が引き起こす細胞死はアポトーシスであり、VacA毒素によるBaxおよびBakの活性化にによつてミトコンドリア障害が引き起こされることが判明した。
  • 文部科学省:科学研究費補助金(特定領域研究(B), 特定領域研究)
    研究期間 : 2000年 -2004年 
    代表者 : 飯利 太朗, 安田 宏, 大西 洋英, 真嶋 浩聡, 槙田 紀子, 藤田 敏郎
     
    1)G蛋白質シグナルの解析・制御ツールのデザインと解析:G蛋白質活性化モデルに基づき、レセプター、βγを標的としこれを抑制するGα変異体を作製してきた。これまでの解析を応用して、各Gαの変異体のデザインを改良、作製した。(1)新しいG蛋白質病で発見された、自体シグナルに対し抑制的に作用する(αs-AVDT)の解析で得られた知見を加え、デザインを改良、各Gαで相同な変異体を作成した。(2)各G蛋白質変異体を遺伝子導入し、各G蛋白質の下流シグナルの解析を行った。2)心肥大・心不全に関連するG蛋白質シグナルの解析と制御:(1)メカニカルストレスにより、AT1レセプターがアンジオテンシンII非依存性に自立的に活性化されることを明らかにした。(2)ある種のAT1レセプターブロッカーがインバースアゴニストとして作用することによって、この自律的活性化を抑制することを明らかにした。新しいレセプターの活性化機構と制御機構として普遍性を有すると考えられる。3)心肥大・心不全モデル系への遺伝子導入:遺伝子導入による制御・治療を展望して、G蛋白質変異体を、心肥大・高血圧などのモデル系の細胞/動物へ、アデノウイルスを用いて遺伝子導入し、効果を検討した。(1)レセプターシグナルと抑制:作製した変異体を用いた抑制を行った。(2)レセプターシグナルの脱感作抑制:レセプターキナーゼによる脱感作を抑制する遺伝子導入を行い、特にβγの抑制による効果を明らかにした。以上より、モデル細胞と、心肥大・心不全モデルマウスへの遺伝子導入への応用を行った。
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 1997年 -1999年 
    代表者 : 小島 至, 真嶋 浩聡, 柴田 宏, 張 有青, 真嶋 浩聡
     
    我々は膵共通前駆細胞に類似した性質をもつ膵AR42J細胞を用いて、β細胞の分化に関与する分化誘導因子の研究を行ってきたが、その中でベータセルリンとアクチビンという2種類の因子がβ細胞への分化誘導能をもつことを明らかにしてきた。そこで、まずこれらの因子が実際に膵部分切除後の膵再生の過程でどのように発現するかについて、免疫組織化学法により検討を行った。その結果、アクチビンは膵導管細胞〜内分泌細胞に、またべ一タセルリンは分化した内分泌細胞に発現が認められることが判明した。この結果はこれら因子が膵再生に関与していることを示唆し、さらにこれらの因子を投与することにより膵β細胞の再生を促進することが出来ることを示唆している。そこで90%膵部分切除モデルを用いてこれらの因子が膵再生を促進できるかどうかを検討した。アクチビンの投与はこれまでに検討した限りでは有効な結果を得ることが出来なかった。アクチビン投与によりアポトーシス誘導が見られるからである。一方、ベータセルリンの投与により、膵部分切除後の膵導管細胞の増殖、膵導管細胞内のPDX-1発現細胞の増加が認められ、さらにインスリン含量の増加、膵島面積の増加が認められた。加えて耐糖能も改善し、血中インスリン濃度も増加した。再生への有効性が初めて確認された。
  • 文部科学省:科学研究費補助金(奨励研究(A))
    研究期間 : 1997年 -1998年 
    代表者 : 真嶋 浩聡
     
    (1)野生株(2)デキサメサゾン処理(3)アクチビンA処理(4)アクチビンA+ベータセルリン処理したAR42J細胞から総RNAを抽出し、mRNA Differential Display法を用いて発現レベルの変化する遺伝子を同定し、その塩基配列を決定した。ノザンブロットを用いて発現レベルの変化を時間的、量的に詳細に検討し、その中で膵の分化に深く関与する遺伝子を(2)より11個、(3)より7個、(4)より20個同定した。情報伝達に関与する蛋白、膜蛋白、分泌蛋白、細胞骨格構成蛋白等の既知の遺伝子の他に未知の遺伝子も数多く得られた。膵の分化を調節する情報伝達系はほとんど解明されていないが、AR42J細胞のインスリン産生細胞への分化はMAPKKの阻害剤PD098059によって抑制された。すなわち膵内分泌細胞への分化にはMAP kinase cascadeの情報伝達系が重要であることが示唆された。そこで、AR42J細胞がインスリン産生細胞へ分化する過程で発現レベルが上昇する(4)より得られた20個の遺伝子の中でPD098059によって発現が抑制されるものは分化に深く関与していると考えられ、ノザンブロットで検討したところ13個の遺伝子の発現が抑制された。この中で未知の遺伝子は5個あり、その中でも特に変化の著しい3個の遺伝子をcDNAライブラリーよりクローニングした。2個はbrain-specific sodium phosphate cotransporter、tricarboxylate carrier proteinとホモロジーをもつ遺伝子であり、1個は全く未知の遺伝子であった。現在これらの遺伝子がコードする蛋白の機能解析を進めている。
  • 文部科学省:科学研究費補助金(基盤研究(B))
    研究期間 : 1996年 -1997年 
    代表者 : 小島 至, 真嶋 浩聡, 柴田 宏
     
    1)膵共通前駆細胞に類似した性質をもつAR42J細胞をアクチビンAによって膵ポリペプチドを産生する内分泌細胞に分化させられること,さらにベータセルリンを作用させることによりインスリン産生細胞へと分化させられることを明らかにし,膵内分泌細胞の分化過程を検討するモデル系を確立した。2)このAR42J細胞を用いて,肝細胞増殖因子(HGF)にベータセルリンと同様の分化誘導作用があることを明らかにした。さらにHGFによく反応してインスリン産生細胞へと分化するサブクローンを確立した。3)アクチビンAが膵内分泌細胞において2つの独立した情報伝達系路を活性化することを明らかにした。4)膵AR42J細胞には,ベータセルリンの特異的な受容体があること,クロスリンク実験によりベータセルリンは分子量180KDaと190KDaの膜蛋白に結合すること,この180KDa蛋白はEGF受容体であるErbB1であるが,190KDa蛋白は既知の抗ErbB抗体によっては認識できない新たな蛋白であること,ベータセルリンによってErbB1,ErbB4とともに190KDa蛋白がチロシン燐酸化されること、ベータセルリンの作用はEGFで十分には再現されないことからおそらくErbB1とともに190KDa蛋白を介して分化シグナルが伝達されることなどを明らかにした。5)AR42J細胞においてHGFおよびベータセルリンはMAPキナーゼを活性化させること,MAPキナーゼを抑制するPD098059やMAPキナーゼフォスファターゼ遺伝子を導入することにより分化が抑制させること,構成的活性型のMAPキナーゼキナーゼ遺伝子を導入すると分化が観察されることなどを見出し,インスリンへ細胞の分化にMAPキナーゼ経路が重要であることを明らかにした。6)アクチビン作用をブロックする変異アクチビン受容体を過剰発現するトランスジェニックマウスを樹立した。このマウスにおいては膵内分泌細胞の分化が抑制されているだけでなく,外分泌細胞にも分化異常が認められ,アクチビンあるいは類似の因子が膵内分泌腺細胞,外分泌腺細胞の分化に重要であることを明らかにした。
  • 文部科学省:科学研究費補助金(奨励研究(A))
    研究期間 : 1996年 -1996年 
    代表者 : 真嶋 浩聡
     
    【目的】膵の分化における誘導遺伝子の同定【方法】A野生株、Bデキサメサゾン処理、CアクチビンA処理、DアクチビンA+ベータセルリン処理したAR42J細胞からmRNA Differential Display法によりこの細胞が外分泌細胞、内分泌細胞として分化する際にどのような遺伝子の発現レベルが変化するかを検討した。【成績】発現レベルが変化する70個のバンドを得た。Bで発現レベルが増加するものが19個(1)、低下するものが10個(2)、Cで発現レベルが増加するバンド15個(3)、低下するバンド5個(4)、Dで発現レベルが増加するバンド20個(5)、低下するバンド1個(6)であった。既知のものは(1)1個(acidic ribosomal phosphoprotein P1)、(2)2個(14-3-3 eta,thymosin beta 10)、(3)5個(β-actin,r-actin,neuron specific enolase,cartilage-derived retinoic acid-sensitive protein,copper/zinc superoxide dismutase)、(4)1個(ubiquitin-like protein)、(5)4個(PTHrP,hemopexin,nerve growth factor-induced gene,mitochondrial cytochrome oxidase)、(6)1個(PACE4)であり、情報伝達に関わる蛋白、転写因子、細胞骨格を構成する蛋白等をコードする遺伝子であった。他は未知の遺伝子であった。【結論】膵の分化を検討する上で、mRNA Differential Display法は発現レベルが変化する遺伝子を効率よく同定し、分化誘導に重要な未知遺伝子を単離するのに非常に有力な方法である。
  • 文部科学省:科学研究費補助金(奨励研究(A))
    研究期間 : 1995年 -1995年 
    代表者 : 真嶋 浩聡
     
    アクチビン受容体にはI型、II型が存在する。受容体I,IB型cDNA、受容体II,IIB型cDNAを利用して発現ベクターを作製した。ヒト肝癌細胞株に発現ベクターを形質導入し、耐性薬剤を利用して単一のクローンを得た。ノザンブロッティングにより受容体のmRNAが発現していることを確認し、[^<125>I]アクチビンAを用いた結合実験により作られた蛋白が受容体として正しく機能していることを確認した。[^<125>I]アクチビンAが結合するためにはII型、またはI型+II型の発現が必要であり、I型のみでは結合しなかった。これらの細胞株を用いてアクチビンAによる増殖抑制効果を検討した。増殖抑制効果は細胞数、DNA量の経時的変化、[^3H]thymidineの取り込みを指標として測定した。しかしヒト肝癌細胞株PCL/PRF/5, Huh7, HLEの3株ともアクチビン受容体を発現させた後もアクチビンAによる増殖抑制効果は全くみられなかった。以上からアクチビンA不応性の原因は受容体以降のステップにあることが示された。アクチビンの細胞内の情報伝達機構はほとんどわかっていないが、TGF-βはサイクリン依存性キナーゼの活性を抑え、RB蛋白のリン酸化を抑制して増殖抑制作用を示すことがわかってきた。そこで形質導入したPCL/PRF/5細胞のRB蛋白のリン酸化の程度をアクチビンAの有無で検討したところ、アクチビンAによるRB蛋白のリン酸化の抑制は見られなかった。今回検討したヒト肝癌細胞株のアクチビンA不応性の原因は、受容体とRB蛋白の間のシグナルの異常にあると考えられた。


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