Research Projects of Competitive Funds, etc. - Hashimoto, Hisayuki

Studying Molecular Mechanisms in Organ Development and Disease Onset Using Cellular Reprogramming

2025.04

-

2028.03

基盤研究(B), Principal investigator

細胞移植療法の最適化に向けた生体内移植細胞の非侵襲的検出技術の開発

2023.06

-

2026.03

日本学術振興会, Grants-in-Aid for Scientific Research, Grant-in-Aid for Challenging Research (Exploratory), No Setting

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細胞移植療法はがんのみならず、様々な分野での臨床応用が期待されている。このような中、我々はヒトにおいて生体内の移植細胞を非侵襲的に評価できるシステムがあれば、臨床試験の成果をより有効に活用し、細胞移植療法の改善点を明らかにできると考えた。
よって、本研究の目的はヒトiPS細胞に特異的なマーカー蛋白を発現させ、このマーカーを非侵襲的な方法で検出する事により、移植した細胞を生体内で非侵襲的に評価する方法を確立する事である。

Dissecting the transcriptional network of organogenesis based on reprogramming factors

2022.04

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2025.03

Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research, Grant-in-Aid for Scientific Research (B), No Setting

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我々は線維芽細胞から心筋細胞を作製する直接分化転換法の研究において、幹細胞の多能性維持に働く転写因子Zfp281に非常に強い心筋分化転換作用がある事を見出した。そして予備実験においてZfp281が心筋分化と心臓発生に必須な因子であることも示唆されている。
よって、本研究ではこのZfp281と心臓形成の予想外な関連性に着目し、様々な遺伝子改変マウス及び遺伝子発現・エピゲノム解析を用いて、Zfp281を中心とした心臓形成の新たな転写制御機構を明らかにする。そして、最終的には研究成果を心疾患の新たな分子機序解明や心臓再生技術の開発へと発展させることを目指す。

中胚葉において循環器形成細胞が誘導される分子基盤解明

2022

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2023

公益財団法人 循環器病研究振興財団, 山内進循環器病研究助成, Principal investigator

エピゲノム編集による心筋分化転換法の確立

2021

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2023

日本循環器学会, 基礎研究助成, Principal investigator

SARS-CoV-2 細胞侵入受容体の発現調節経路を標的としたCOVID-19 の新規治療戦略

2020

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2021

公益財団法人 東京生化学研究会, 研究奨励金, Principal investigator

Synergistic Activation of the Cardiac Enhancer Landscape During Reprogramming

2019.09

The Ichiro Kanehara Foundation, Grant-in-Aid for Research Exchange, Hisayuki Hashimoto, Principal investigator

Dissecting the cardiogenic network of ZNF281

2019.04

-

2022.03

Keio University, Grants-in-Aid for Scientific Research, Hashimoto Hisayuki, Grant-in-Aid for Early-Career Scientists, Research grant, Principal investigator

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During direct cardiac reprogramming, cardiogenic TFs cooperatively reshape the epigenomic landscape by activating cardiac enhancers, which describe a common epigenetic signature between in vitro cardiac reprogramming and in vivo heart development. We thus hypothesized that direct reprogramming could be a useful tool to study novel transcriptional regulators in heart development. To test this hypothesis, we focused on ZNF281, which showed up as an unexpected strong cardiac reprogramming inducer from our previous unbiased screen.
By using multiple genetic mouse models, we discovered that cardiac reprogramming inducer ZNF281 plays a pivotal role in heart development. We generated different stage-specific ZNF281KO mouse lines and found that mesodermal ZNF281KO mice were embryonic lethal as early as E9.5, associated with various cardiac anomalies. Our study demonstrates and highlights the impact and possibility of direct reprogramming as a novel approach to study cardiovascular biology.

リプログラミング法を利用した新たな心臓形成転写ネットワークの探索

2019

-

2021

公益財団法人　持田記念医学薬学振興財団, 研究助成, 研究助成, Research grant, Principal investigator

オルガノイド形成に向けた心臓刺激伝導系転写制御機構の解明

2019

-

2021

公益財団法人　MSD生命科学財団, 生活習慣病領域, 研究助成, Research grant, Principal investigator

リプログラミング法を利用した心臓刺激伝導系誘導因子の探索

2019

-

2021

Takeda Science Foundation, Grant-in-Aid for Medical Research, Hisayuki Hashimoto, 研究助成, Research grant, Principal investigator

エピゲノム解析と分化転換による⼼筋分化誘導法の確立

2019

-

2021

公益財団法人　アステラス病態代謝研究会, 研究助成金, 研究助成, Research grant, Principal investigator

リプログラミング法を利用した新たな心臓形成転写ネットワークの探索

2019

-

2021

公益財団法人　持田記念医学薬学振興財団, 研究助成, 研究助成, Research grant, Principal investigator

エピゲノム解析と分化転換を利用した新たな心筋分化機構の解明

2019

-

2020

公益財団法人 先進医薬研究振興財団, 循環医学分野研究助成, 研究助成, Research grant, Principal investigator

リプログラミング法を利用した新たな心臓形成転写ネットワークの探索

2019

-

2020

慶應義塾大学, 坂口光洋記念慶應義塾医学振興基金, 研究助成, Research grant, Principal investigator

Induction of Diverse Cardiac Cell Types by Direct Reprogramming

2016

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2017

The Kanae Foundation for the Promotion of Medical Science, Grant-in-Aid for Oversea Research, Hashimoto Hisayuki, Principal investigator

Exploring the role of cell cycle regulators in heart failure

2015

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2017

The Uehara Memorial Foundation, Overseas Postdoctoral Fellowship, 研究助成, Research grant, Principal investigator

Disease Modeling for Mitochondrial Disease Using MELAS Specific Induced Pluripotent Stem Cells

2013.04

-

2015.03

Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Young Scientists (B), KODAIRA Masaki, YUASA Shinsuke, EGASHIRA Toru, HASHIMOTO Hisayuki, KUSUMOTO Dai, KUNITOMI Akira, KASHIMURA Shin, YUASA Shinsuke, EGASHIRA Toru, HASHIMOTO Hisayuki, KUSUMOTO Dai, KUNITOMI Akira, KASHIMURA Shin, Grant-in-Aid for Young Scientists (B), Coinvestigator(s)

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We successfully established iPSCs from MELAS- fibroblasts. MELAS is one of the most common mitochondrial disease and there are no effective ways to cure the disease at the moment. MELAS-iPSC lines ranged from 3.6% to 99.4% of m.3243A>G heteroplasmy levels. The enzymatic activities of mitochondrial respiratory complexes indicated that MELAS-iPSC-derived fibroblasts with high heteroplasmy levels showed a deficiency of complex I activity but MELAS-iPSC-derived fibroblasts with low heteroplasmy levels showed normal complex I activity. Our data indicate that MELAS-iPSCs can be models for MELAS but we should carefully select MELAS-iPSCs with appropriate heteroplasmy levels and respiratory functions for mitochondrial disease modeling.

The role of geminin in cardiomyocyte cell cycle

2013

-

2014

Keio University, Grant-in-Aid for Encouragement of Young Medical Scientists, Hisayuki Hashimoto, Principal investigator

Exploring a novel cardiomyocyte cell cycle regulator by utilizing a fluorescent ubiquitination-based cell cycle indicator

2012.08

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2014.03

Japan Society for the Promotion of Science, Grants-in-Aid for Scientific Research Grant-in-Aid for Research Activity Start-up, HASHIMOTO Hisayuki, Grant-in-Aid for Research Activity Start-up, Principal investigator

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The minimal capacity of mature cardiomyocte regeneration is one of the factors which determines the poor prognosis of heart failure. If we can proliferate cardiomyocytes and regenerate the heart, we will be able to completely cure heart failure. We planned to explore a novel cardiomyocyte cell cycle regulator by utilizing a fluorescent ubiquitination-based cell cycle indicator. We identified a protein which the expression level changes during the proliferation phase of cell cycle. We are analyzing the function of this candidate protein by over-expressing and deleting it in cardiomyocyte.

The establishment of a live imaging method for cardiomyocyte cell cycle analysis

2012

-

2013

Keio University, Grant-in-Aid for Encouragement of Young Medical Scientists, Hisayuki Hashimoto, Principal investigator

The exploration of a novel mechanism in regenerating cardiomyocyte after myocardial infarction

2011.04

-

2012.03

Keio University, Graduate School Doctoral Student Aid Program, Hisayuki Hashimoto, Principal investigator

心筋細胞におけるDcppの細胞周期調節機構の解明

2010

-

2011

慶應義塾大学, 医学部研究奨励費, Principal investigator