基本情報
- 所属
- 自治医科大学 医学部 客員教授
- 学位
- 医学博士(自治医科大学)
- ORCID ID
https://orcid.org/0000-0002-3185-7790
- J-GLOBAL ID
- 200901074911542236
- researchmap会員ID
- 1000063389
神経疾患の遺伝子治療を開発しています。
研究キーワード
14経歴
6-
2024年4月 - 現在
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2008年11月 - 現在
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2019年4月 - 2024年3月
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2019年4月 - 2024年3月
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2014年11月 - 2019年3月
委員歴
2-
- 現在
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- 2019年5月
受賞
4-
2019年3月
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2011年7月
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2009年6月
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2000年6月
論文
366-
HUMAN MOLECULAR GENETICS 25(20) 4432-4447 2016年10月 査読有りDNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (gamma H2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice. All these results suggested a possibility of gene therapy with RpA1 for SCA1.
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Hum. Mol. Genet. 2016年8月 査読有りDNA damage and repair is a critical domain of many neurodegenerative diseases. In this study, we focused on RpA1, a candidate key molecule in polyQ disease pathologies, and tested the therapeutic effect of adeno-associated virus (AAV) vector expressing RpA1 on mutant Ataxin-1 knock-in (Atxn1-KI) mice. We found significant effects on motor functions, normalized DNA damage markers (γH2AX and 53BP1), and improved Purkinje cell morphology; effects that lasted for 50 weeks following AAV-RpA1 infection. In addition, we confirmed that AAV-RpA1 indirectly recovered multiple cellular functions such as RNA splicing, transcription and cell cycle as well as abnormal morphology of dendrite and dendritic spine of Purkinje cells in Atxn1-KI mice. All these results suggested a possibility of gene therapy with RpA1 for SCA1.
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Human molecular genetics 2016年8月 査読有り
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SCIENCE TRANSLATIONAL MEDICINE 8(347) 347ra94 2016年7月 査読有りSpinocerebellar ataxia type 6 (SCA6) is a dominantly inherited neurodegenerative disease characterized by slowly progressive ataxia and Purkinje cell degeneration. SCA6 is caused by a polyglutamine repeat expansion within a second CACNA1A gene product, alpha 1ACT. alpha 1ACT expression is under the control of an internal ribosomal entry site (IRES) present within the CACNA1A coding region. Whereas SCA6 allele knock-in mice show indistinguishable phenotypes from wild-type littermates, expression of SCA6-associated alpha 1ACT (alpha 1ACT(SCA6)) driven by a Purkinje cell-specific promoter in mice produces slowly progressive ataxia and cerebellar atrophy. We developed an early-onset SCA6 mouse model using an adeno-associated virus (AAV)-based gene delivery system to ectopically express CACNA1A IRES-driven alpha 1ACT(SCA6) to test the potential of CACNA1A IRES-targeting therapies. Mice expressing AAV9-mediated CACNA1A IRES-driven alpha 1ACT(SCA6) exhibited early-onset ataxia, motor deficits, and Purkinje cell degeneration. We identified miR-3191-5p as a microRNA (miRNA) that targeted CACNA1A IRES and preferentially inhibited the CACNA1A IRES-driven translation of a1ACT in an Argonaute 4 (Ago4)-dependent manner. We found that eukaryotic initiation factors (eIFs), eIF4AII and eIF4GII, interacted with the CACNA1A IRES to enhance alpha 1ACT translation. Ago4-bound miR-3191-5p blocked the interaction of eIF4AII and eIF4GII with the CACNA1A IRES, attenuating IRES-driven alpha 1ACT translation. Furthermore, AAV9-mediated delivery of miR-3191-5p protected mice from the ataxia, motor deficits, and Purkinje cell degeneration caused by CACNA1A IRES-driven alpha 1ACT(SCA6). We have established proof of principle that viral delivery of an miRNA can rescue a disease phenotype through modulation of cellular IRES activity in a mouse model.
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A novel reporter rat strain that conditionally expresses the bright red fluorescent protein tdTomatoPLoS ONE 11(5) e0155687 2016年5月1日 査読有りDespite the strength of the Cre/loxP recombination system in animal models, its application in rats trails that in mice because of the lack of relevant reporter strains. Here, we generated a floxed STOP tdTomato rat that conditionally expresses a red fluorescent protein variant (tdTomato) in the presence of exogenous Cre recombinase. The tdTomato signal vividly visualizes neurons including their projection fibers and spines without any histological enhancement. In addition, a transgenic rat line (FLAME) that ubiquitously expresses tdTomato was successfully established by injecting intracytoplasmic Cre mRNA into fertilized ova. Our rat reporter system will facilitate connectome studies as well as the visualization of the fine structures of genetically identified cells for long periods both in vivo and ex vivo. Furthermore, FLAME is an ideal model for organ transplantation research owing to improved traceability of cells/tissues.
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Journal of nuclear medicine : official publication, Society of Nuclear Medicine 57(2) 303-308 2016年2月 査読有り
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The International Journal of Neuropsychopharmacology 2016年
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Scientific Online Letters on the Atmosphere 2016年
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Journal of Pharmacological Sciences 2016年
MISC
214共同研究・競争的資金等の研究課題
17-
日本学術振興会 科学研究費助成事業 2022年6月 - 2025年3月
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日本学術振興会 科学研究費助成事業 2020年4月 - 2023年3月
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日本学術振興会 科学研究費助成事業 2016年4月 - 2018年3月
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日本学術振興会 科学研究費助成事業 2015年4月 - 2018年3月
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日本学術振興会 科学研究費助成事業 2015年4月 - 2017年3月