分子病態治療研究センター

水上 浩明

ミズカミ ヒロアキ  (Hiroaki Mizukami)

基本情報

所属
自治医科大学 分子病態治療研究センター 遺伝子治療研究部 教授
学位
医学博士(自治医科大学(JMU))
M.D.

J-GLOBAL ID
200901034663759310
researchmap会員ID
1000273320

外部リンク

学歴

 1

論文

 187
  • Jun Noguchi, Satoshi Watanabe, Tomofumi Oga, Risa Isoda, Keiko Nakagaki, Kazuhisa Sakai, Kayo Sumida, Kohei Hoshino, Koichi Saito, Izuru Miyawaki, Eriko Sugano, Hiroshi Tomita, Hiroaki Mizukami, Akiya Watakabe, Tetsuo Yamamori, Noritaka Ichinohe
    Communications biology 7(1) 642-642 2024年5月27日  
    Alterations in the experience-dependent and autonomous elaboration of neural circuits are assumed to underlie autism spectrum disorder (ASD), though it is unclear what synaptic traits are responsible. Here, utilizing a valproic acid-induced ASD marmoset model, which shares common molecular features with idiopathic ASD, we investigate changes in the structural dynamics of tuft dendrites of upper-layer pyramidal neurons and adjacent axons in the dorsomedial prefrontal cortex through two-photon microscopy. In model marmosets, dendritic spine turnover is upregulated, and spines are generated in clusters and survived more often than in control marmosets. Presynaptic boutons in local axons, but not in commissural long-range axons, demonstrate hyperdynamic turnover in model marmosets, suggesting alterations in projection-specific plasticity. Intriguingly, nasal oxytocin administration attenuates clustered spine emergence in model marmosets. Enhanced clustered spine generation, possibly unique to certain presynaptic partners, may be associated with ASD and be a potential therapeutic target.
  • Yoshihide Sehara, Yuki Hashimotodani, Ryota Watano, Kenji Ohba, Ryosuke Uchibori, Kuniko Shimazaki, Kensuke Kawai, Hiroaki Mizukami
    Molecular neurobiology 2024年4月27日  
    It is established that neurogenesis of dentate gyrus is increased after ischemic insult, although the regulatory mechanisms have not yet been elucidated. In this study, we focused on Ezh2 which suppresses gene expression through catalyzing trimethylation of lysine 27 of histone 3. Male gerbils were injected with adeno-associated virus (AAV) carrying shRNA targeting to Ezh2 into right dentate gyrus 2 weeks prior to forebrain ischemia. One week after ischemia, animals were injected with thymidine analogue to label proliferating cells. Three weeks after ischemia, animals were killed for histological analysis. AAV-mediated knockdown of Ezh2 significantly decreased the ischemia-induced increment of proliferating cells, and the proliferated cells after ischemia showed significantly longer migration from subgranular zone (SGZ), compared to the control group. Furthermore, the number of neural stem cells in SGZ significantly decreased after ischemia with Ezh2 knockdown group. Of note, Ezh2 knockdown did not affect the number of proliferating cells or the migration from SGZ in the non-ischemic condition. Our data showed that, specifically after ischemia, Ezh2 knockdown shifted the balance between self-renewal and differentiation toward differentiation in adult dentate gyrus.
  • Yuka Hayashi, Yoshihide Sehara, Ryota Watano, Kenji Ohba, Yuki Takayanagi, Yoshio Sakiyama, Kazuhiro Muramatsu, Hiroaki Mizukami
    Human Gene Therapy 2024年2月22日  
  • Keitaro Obara, Teppei Ebina, Shin-Ichiro Terada, Takanori Uka, Misako Komatsu, Masafumi Takaji, Akiya Watakabe, Kenta Kobayashi, Yoshito Masamizu, Hiroaki Mizukami, Tetsuo Yamamori, Kiyoto Kasai, Masanori Matsuzaki
    Nature Communications 14(1) 2023年11月13日  
    Abstract Although cortical feedback signals are essential for modulating feedforward processing, no feedback error signal across hierarchical cortical areas has been reported. Here, we observed such a signal in the auditory cortex of awake common marmoset during an oddball paradigm to induce auditory duration mismatch negativity. Prediction errors to a deviant tone presentation were generated as offset calcium responses of layer 2/3 neurons in the rostral parabelt (RPB) of higher-order auditory cortex, while responses to non-deviant tones were strongly suppressed. Within several hundred milliseconds, the error signals propagated broadly into layer 1 of the primary auditory cortex (A1) and accumulated locally on top of incoming auditory signals. Blockade of RPB activity prevented deviance detection in A1. Optogenetic activation of RPB following tone presentation nonlinearly enhanced A1 tone response. Thus, the feedback error signal is critical for automatic detection of unpredicted stimuli in physiological auditory processing and may serve as backpropagation-like learning.
  • Kenta Fujimura, Tadayoshi Karasawa, Takanori Komada, Naoya Yamada, Yoshiko Mizushina, Chintogtokh Baatarjav, Takayoshi Matsumura, Kinya Otsu, Norihiko Takeda, Hiroaki Mizukami, Kazuomi Kario, Masafumi Takahashi
    Journal of molecular and cellular cardiology 180 58-68 2023年7月  
    Sepsis is a life-threatening syndrome, and its associated mortality is increased when cardiac dysfunction and damage (septic cardiomyopathy [SCM]) occur. Although inflammation is involved in the pathophysiology of SCM, the mechanism of how inflammation induces SCM in vivo has remained obscure. NLRP3 inflammasome is a critical component of the innate immune system that activates caspase-1 (Casp1) and causes the maturation of IL-1β and IL-18 as well as the processing of gasdermin D (GSDMD). Here, we investigated the role of the NLRP3 inflammasome in a murine model of lipopolysaccharide (LPS)-induced SCM. LPS injection induced cardiac dysfunction, damage, and lethality, which was significantly prevented in NLRP3-/- mice, compared to wild-type (WT) mice. LPS injection upregulated mRNA levels of inflammatory cytokines (Il6, Tnfa, and Ifng) in the heart, liver, and spleen of WT mice, and this upregulation was prevented in NLRP3-/- mice. LPS injection increased plasma levels of inflammatory cytokines (IL-1β, IL-18, and TNF-α) in WT mice, and this increase was markedly inhibited in NLRP3-/- mice. LPS-induced SCM was also prevented in Casp1/11-/- mice, but not in Casp11mt, IL-1β-/-, IL-1α-/-, or GSDMD-/- mice. Notably, LPS-induced SCM was apparently prevented in IL-1β-/- mice transduced with adeno-associated virus vector expressing IL-18 binding protein (IL-18BP). Furthermore, splenectomy, irradiation, or macrophage depletion alleviated LPS-induced SCM. Our findings demonstrate that the cross-regulation of NLRP3 inflammasome-driven IL-1β and IL-18 contributes to the pathophysiology of SCM and provide new insights into the mechanism underlying the pathogenesis of SCM.

MISC

 169

書籍等出版物

 1

共同研究・競争的資金等の研究課題

 29

産業財産権

 2