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OISHI Hisashi

    Graduate School of Medical Sciences Department of Comparative and Experimental Medicine　Professor
Contact： hoishimed.nagoya-cu.ac.jp
Last Updated :2024/04/24

Researcher Information

URL

J-Global ID

Research Interests

  • Disease Model   Reproductive Medicine   Embryology   

Research Areas

  • Life sciences / Laboratory animal science
  • Life sciences / Anatomy

Academic & Professional Experience

  • 2016/11 - Today  Nagoya City UniversityGraduate School of Medical SciencesProfessor

Association Memberships

  • 日本生化学会   日本分子生物学会   日本解剖学会   日本実験動物学会   

Published Papers

Conference Activities & Talks

  • Generation and Characterization of Reporter Mice to Monitor Pdx1 and Mafa Promoter Activity  [Not invited]
    Wataru Nishimura; Nobuaki Funahashi; Haruhide Udagawa; Miho Kawaguchi; Takao Nammo; Hisashi Oishi; Satoru Takahashi; Kazuki Yasuda
    ENDOCRINE REVIEWS  2014/06  ENDOCRINE SOC
  • Bioluminescence Imaging of Novel BAC Transgenic Mice Expressing Luciferase Reporter Under the Control of the Insulin Locus  [Not invited]
    Hisashi Oishi; Tokio Katsumata; Yukari Sekiguchi; Haruka Nagasaki; Masatsugu Ema; Takashi Kudo; Satoru Takahashi
    DIABETES  2012/06  AMER DIABETES ASSOC

MISC

Research Grants & Projects

  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2023/04 -2026/03 
    Author : 大石 久史; 齋藤 伸治; シャウキ ホッサム
  • 日本学術振興会：科学研究費助成事業
    Date (from‐to) : 2022/04 -2026/03 
    Author : 杉浦 真弓; 奥野 友介; 松浦 栄次; 大石 久史
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2020/04 -2024/03 
    Author : 齋藤 伸治; 加藤 洋一; 大石 久史; 嶋田 逸誠; 宮 冬樹
     
    巨脳症患者を対象としたパネル解析を引き続き実施し、2021年度は9例に実施した。その結果、PTEN遺伝子変異を2例、PIK3CA変異モザイク例を1例同定した。患者情報として臨床情報とMRIを収集し、遺伝子変異情報と共にデータベースを更新した。 脳オルガノイドを用いた実験では、正常iPS細胞から遺伝子編集を行い、PNPLA8、SZT2、MYCNの機能喪失型変異を導入し、脳オルガノイドの作成を行った。脳オルガノイドにおいては皮質発生を再現することができた。特に、PNPLA8のKO脳オルガノイドについて詳しく検討ができ、脳皮質形成障害の原因として外側ラジアルグリア（oRG）の分裂能が低下していることを明らかにした。さらにその原因としてミトコンドリア機能の障害を明らかにした。これらの実験によりiPS細胞から脳オルガノイドを作成し、脳皮質発生に関する一連の実験を行う実験系を確立した。 さらに、ヒト患者からのiPS細胞の作成をPNPLA8およびMYCNに変異を有する患者から行った。PNPNL8患者由来iPS細胞の樹立に成功し、さらに脳オルガノイドを作成し、患者にみられた病態の再現に成功した。さらに、遺伝子改変iPS細胞由来の脳オルガノイドと表現型が共通することを確認した。MYCNについては現在実験が進行中である。 モデルマウスとしては引き続き、MYCNの機能亢進型変異および機能喪失型変異マウスについての解析を行った。機能亢進型モデルマウスではヒト患者で見られた巨脳症が再現され、その原因として胎生期の神経幹細胞の分化と増殖のバランスが乱れることと神経細胞の遊走が関連することを明らかにした。上述した患者由来iPS細胞を用いた脳オルガノイド実験と組み合わせることで、病態の改名の基盤を構築することができた。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)
    Date (from‐to) : 2020/07 -2022/03 
    Author : Saitoh Shinji
     
    We have identified three new cases of VPS35L-related Ritscher-Schinzel syndrome (RSS), one Japanese, one French, and one Dutch case, and delineated clinical features. This is the largest collection of patients with VPS35L-related RSS, and now we have established the new clinical entity of VPS35L-related RSS. Regarding Schaaf-Yang syndrome (SYS), we have collected detailed clinical information from 25 Japanese patients with genetically confirmed SYS. We also successfully established tissue specific conditional knock-out mice (central nervous system and mesenchymal stem cell), and recapitulate clinical features of VPS35L-related RSS. Using the mouse models, we successfully identified altered expression of membrane integral proteins.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (B)
    Date (from‐to) : 2019/04 -2022/03 
    Author : Tanaka Yasuhito
     
    Liver fibrosis is an important risk factor for the development of hepatocellular carcinoma (HCC) in patients with after hepatitis C virus (HCV) eradication or with steatohepatitis. In this study, we investigated the mechanisms of liver fibrosis and hepatocarcinogenesis by TGFβ and TLL1, as well as by miR-6133-5p, which suppresses collagen gene expression. MiR-6133-5p was found to inhibit phosphorylation of major intracellular signal transduction pathways and act upstream of JNK. In addition, we have established lines of transgenic mice with the hepatocyte-specific overexpression of hTLL1. For siRNA-loaded lipid nanoparticles (LNP) by iLiNP microfluidic device, we identified the optimal LNPs and verified the safety in mouse liver.
  • 日本学術振興会：科学研究費助成事業 基盤研究(C)
    Date (from‐to) : 2018/04 -2021/03 
    Author : 杉浦 真弓; 大石 久史
     
    流死産を繰り返す不育症の原因は抗リン脂質抗体、染色体均衡型転座、子宮奇形、胎児染色体数的異常である。本研究では、真の原因不明で10回以上繰り返す難治性習慣流産Super流産患者とその両親のトリオ解析とマウスゲノム編集による新しい手法により原因遺伝子を同定する。 5家系の全エクソントリオ解析を行った。非同義置換、スプライス変異、ストップゲイン、フレームシフト変異に着目し、各患者に13-27候補遺伝子を絞り込んだ。各家系に共通の遺伝子はみられなかった。TDRD15, RUFY3（家系4）に、PIPTNM1, OR9K2（家系2）にサンガー法により新規変異を確認した。家系1, 4, 7について検体採取を再度行い、成育医療研究センター周産期病態研究部秦健一郎部長により全エクソン解析を行い、研究の方向性についてDiscussionを行った。 RUFY3は、新潟大学五十嵐道弘教授らがRufy3欠損マウス作成を報告したため、共同研究として受精卵の提供を受けた。Rufy3は、スモールGTPaseのアダプタープロテインの一つRap2に結合し、Tiam2/STEFを活性化して、神経極性とアクソン伸長を制御することがわかっている（Honda A et al, J Biol Chem 2017）。全身性のRufy3遺伝子欠損マウスは生直後に死亡してしまうため、ヘテロメスマウスの妊娠、出産について、新潟大学において予備的検討を行った（新潟大が論文準備中）。 Tcf23は、プロゲステロン依存性に子宮内膜間質細胞の脱落膜化に関与することが示唆されている（Kommagani R et al, Biol Reprod 2014）。マウス子宮内膜の免疫染色では、間質細胞特異的にTcf23の発現を認めた。Tcf23遺伝子の機能を調べるために欠損マウスを作製し、ホモ欠損マウスの誕生を確認した。
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Challenging Research (Exploratory)
    Date (from‐to) : 2018/06 -2020/03 
    Author : Saitoh Shinji
     
    We identified a novo c.173C>T mutation in MYCN which leads to stabilization and accumulation of the MYCN protein, leading to prolonged CCND1 and CCND2 expression. This may promote neurogenesis in the developing cerebral cortex, leading to megalencephaly. While loss-of-function mutations in MYCN are known to cause microcephaly, we for the first time uncovered that a germline gain-of-function mutation in MYCN causes a novel megalencephaly syndrome. Additionally, we successfully generated knock-in mice of the identified mutation in MYCN using the CRISPR/Cas9 technology. Our findings provide new insight into the critical role of MYCN in brain development, as well as the consequences of MYCN defects.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research
    Date (from‐to) : 2017/06 -2020/03 
    Author : Oishi Hisashi
     
    The key pathogenesis of diabetes is that glucose cannot be used efficiently in the body due to the absolute and relative deficiency of insulin. In this study, we focused on hepatocytes as a new cell source for regenerating pancreatic β cells, and developed a method for directly inducing insulin production in vivo. We are able to induce insulin gene expression more strongly by co-expressing the Isl1 gene in addition to the previously clarified Pdx1, NeuroD, and MafA genes. It is also cleared that polydatine, which is a resveratrol glycoside, has an inhibitory effect on β-cell death due to oxidative stress.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (A)
    Date (from‐to) : 2015/04 -2018/03 
    Author : SOYA Hideaki
     
    Stress and/or lack of exercise cause lower vitality within our body and mind, especially cause cognitive dysfunction that related to hippocampus. To solve this problem, it is necessary to develop the new exercise prescription for increasing continuously willing on exercise. In this study, the effect of low intensity exercise (LE) and high intensity interval training (HIT) was both examined on human and animals studies. Our results showed that HIT could also enhance cognitive function just as ME did. In addition, acute mild exercise in human also revealed enhanced hippocampal function. Furthermore, LE was also effective for improving cognitive function in the disease animal model of cognitive dysfunction. In summary, our results demonstrated and established the new exercise prescription and is expecting to become the basic concepts for applying to clinical practice in the future.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2014/04 -2017/03 
    Author : OISHI Hisashi
     
    In this study, the functional similarity and difference of large Maf transcription factors has been elucidated in endocrine pancreas. The phenotypic comparison among MafA(-/-), β-cell specific MafB(-/-), and MafA(-/-);MafB(+/-) mice revealed that: (1) MafA gene was important for the maturation of β-cell function but not for β-cell development, (2)conversely, MafB gene was important for the normal β-cell development, and β-cell specific MafB(-/-) mice in adult showed no obvious abnormality including fasting blood glucose levels and glucose stimulated insulin secretion. In addition, in order to apply diabetic treatment of large Maf genes, MafA or MafB gene together with other β-cell related genes were transferred in to mouse liver. The result demonstrated MafA is capable to induce more effective β-like cell induction than MafB.
  • Japan Society for the Promotion of Science：Grants-in-Aid for Scientific Research Grant-in-Aid for Scientific Research (C)
    Date (from‐to) : 2011 -2013 
    Author : OISHI Hisashi; TAKAHASHI Satoru
     
    It is an important research subject to understand the mechanisms of pancreatic beta-cell development and maturation for the achievement of regeneration therapy for diabetes. The project yielded these three results: (1) To analyze the function of large Maf transcription factors in pancreatic endocrine cells, we generated floxed MafB mice. (2) To monitor the newly induced beta-like cells in mouse liver, we established the in vivo imaging system capable to quantify the insulin gene activity (3) Dominant role of MafA in the beta-like cell conversion in comparison with MafB.

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