GODA, Nobuhito

写真a

Affiliation

Faculty of Science and Engineering, School of Advanced Science and Engineering

Job title

Professor

Homepage URL

http://www.waseda.jp/sem-godalab/

Concurrent Post 【 display / non-display

  • Faculty of Science and Engineering   Graduate School of Advanced Science and Engineering

  • Affiliated organization   Global Education Center

Research Institute 【 display / non-display

  • 2020
    -
    2022

    理工学術院総合研究所   兼任研究員

Education 【 display / non-display

  •  
    -
    1997

    Keio University   Graduate School of Medicine  

  •  
    -
    1990

    Keio University   School of Medicine  

Degree 【 display / non-display

  • 慶應義塾大学   博士(医学)

Professional Memberships 【 display / non-display

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    THE JAPAN SOCIETY OF HEPATOLOGY

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    日本微小循環学会

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    日本分子生物学会

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    日本生化学会

 

Research Areas 【 display / non-display

  • Laboratory animal science

  • Gastroenterology   肝臓病

  • Metabolism and endocrinology   糖尿病

  • Pathological biochemistry   低酸素生物学

Research Interests 【 display / non-display

  • 糖尿病

  • 糖・脂質代謝

  • 肝臓病

  • ノックアウトマウス

  • 低酸素応答・低酸素ストレス

Papers 【 display / non-display

  • p38α plays differential roles in hematopoietic stem cell activity dependent on aging contexts.

    Yuriko Sorimachi, Daiki Karigane, Yukako Ootomo, Hiroshi Kobayashi, Takayuki Morikawa, Kinya Otsu, Yoshiaki Kubota, Shinichiro Okamoto, Nobuhito Goda, Keiyo Takubo

    The Journal of biological chemistry     100563 - 100563  2021.03  [International journal]

     View Summary

    Hematopoietic stem cells (HSCs) and their progeny sustain lifetime hematopoiesis. Aging alters HSC function, number, and composition and increases risk of hematological malignancies, but how these changes occur in HSCs remains unclear. Signaling via p38MAPK has been proposed as a candidate mechanism underlying induction of HSC aging. Here, using genetic models of both chronological and premature aging, we describe a multimodal role for p38α, the major p38MAPK isozyme in hematopoiesis, in HSC aging. We report that p38α regulates differentiation bias and sustains transplantation capacity of HSCs in the early phase of chronological aging. However, p38α decreased HSC transplantation capacity in the late progression phase of chronological aging. Furthermore, co-deletion of p38α in mice deficient in Ataxia-telangiectasia mutated (Atm), a model of premature aging, exacerbated aging-related HSC phenotypes seen in Atm single mutant mice. Overall, these studies provide new insight into multiple functions of p38MAPK, which both promotes and suppresses HSC aging context-dependently.

    DOI PubMed

  • In vivo O2 imaging in hepatic tissues by phosphorescence lifetime imaging microscopy using Ir(III) complexes as intracellular probes.

    Kiichi Mizukami, Ayaka Katano, Shuichi Shiozaki, Toshitada Yoshihara, Nobuhito Goda, Seiji Tobita

    Scientific reports   10 ( 1 ) 21053 - 21053  2020.12  [International journal]

     View Summary

    Phosphorescence lifetime imaging microscopy (PLIM) combined with an oxygen (O2)-sensitive luminescent probe allows for high-resolution O2 imaging of living tissues. Herein, we present phosphorescent Ir(III) complexes, (btp)2Ir(acac-DM) (Ir-1) and (btp-OH)3Ir (Ir-2), as useful O2 probes for PLIM measurement. These small-molecule probes were efficiently taken up into cultured cells and accumulated in specific organelles. Their excellent cell-permeable properties allowed for efficient staining of three-dimensional cell spheroids, and thereby phosphorescence lifetime measurements enabled the evaluation of the O2 level and distribution in spheroids, including the detection of alterations in O2 levels by metabolic stimulation with an effector. We took PLIM images of hepatic tissues of living mice by intravenously administrating these probes. The PLIM images clearly visualized the O2 gradient in hepatic lobules with cellular-level resolution, and the O2 levels were derived based on calibration using cultured cells; the phosphorescence lifetime of Ir-1 gave reasonable O2 levels, whereas Ir-2 exhibited much lower O2 levels. Intravenous administration of NH4Cl to mice caused the hepatic tissues to experience hypoxia, presumably due to O2 consumption to produce ATP required for ammonia detoxification, suggesting that the metabolism of the probe molecule might affect liver O2 levels.

    DOI PubMed

  • ZAK Inhibitor PLX4720 Promotes Extrusion of Transformed Cells via Cell Competition.

    Takeshi Maruyama, Ayana Sasaki, Sayuri Iijima, Shiyu Ayukawa, Nobuhito Goda, Keisuke Tazuru, Norikazu Hashimoto, Takashi Hayashi, Kei Kozawa, Nanami Sato, Susumu Ishikawa, Tomoko Morita, Yasuyuki Fujita

    iScience   23 ( 7 ) 101327 - 101327  2020.07  [Refereed]  [International journal]

     View Summary

    Previous studies have revealed that, at the initial step of carcinogenesis, transformed cells are often eliminated from epithelia via cell competition with the surrounding normal cells. In this study, we performed cell competition-based high-throughput screening for chemical compounds using cultured epithelial cells and confocal microscopy. PLX4720 was identified as a hit compound that promoted apical extrusion of RasV12-transformed cells surrounded by normal epithelial cells. Knockdown/knockout of ZAK, a target of PLX4720, substantially enhanced the apical elimination of RasV12 cells in vitro and in vivo. ZAK negatively modulated the accumulation or activation of multiple cell competition regulators. Moreover, PLX4720 treatment promoted apical elimination of RasV12-transformed cells in vivo and suppressed the formation of potentially precancerous tumors. This is the first report demonstrating that a cell competition-promoting chemical drug facilitates apical elimination of transformed cells in vivo, providing a new dimension in cancer preventive medicine.

    DOI PubMed

  • Adrenal cortex hypoxia modulates aldosterone production in heart failure.

    Kaoru Yamashita, Kentaro Ito, Jin Endo, Tomohiro Matsuhashi, Yoshinori Katsumata, Tsunehisa Yamamoto, Kohsuke Shirakawa, Sarasa Isobe, Masaharu Kataoka, Naohiro Yoshida, Shinichi Goto, Hidenori Moriyama, Hiroki Kitakata, Fumiko Mitani, Keiichi Fukuda, Nobuhito Goda, Atsuhiro Ichihara, Motoaki Sano

    Biochemical and biophysical research communications   524 ( 1 ) 184 - 189  2020.03  [Refereed]  [International journal]

     View Summary

    Plasma aldosterone concentration increases in proportion to the severity of heart failure, even during treatment with renin-angiotensin system inhibitors. This study investigated alternative regulatory mechanisms of aldosterone production that are significant in heart failure. Dahl salt-sensitive rats on a high-salt diet, a rat model of heart failure with cardio-renal syndrome, had high plasma aldosterone levels and elevated β3-adrenergic receptor expression in hypoxic zona glomerulosa cells. In H295R cells (a human adrenocortical cell line), hypoxia-induced β3-adrenergic receptor expression. Hypoxia-mediated β3-adrenergic receptor expression augmented aldosterone production by facilitating hydrolysis of lipid droplets though ERK-mediated phosphorylation of hormone-sensitive lipase, also known as cholesteryl ester hydrolase. Hypoxia also accelerated the synthesis of cholesterol esters by acyl-CoA:cholesterol acyltransferase, thereby increasing the cholesterol ester content in lipid droplets. Thus, hypoxia enhanced aldosterone production by zona glomerulosa cells via promotion of the accumulation and hydrolysis of cholesterol ester in lipid droplets. In conclusion, hypoxic zona glomerulosa cells with heart failure show enhanced aldosterone production via increased catecholamine responsiveness and activation of cholesterol trafficking, irrespective of the renin-angiotensin system.

    DOI PubMed

  • Generation of Rat Monoclonal Antibodies Specific for Human Stromal Cell-Derived Factor-2.

    Masako Tanaka, Masayuki Shiota, Masaru Koyama, Jun Nakayama, Masakazu Yashiro, Kentaro Semba, Nobuhito Goda

    Monoclonal antibodies in immunodiagnosis and immunotherapy   39 ( 1 ) 23 - 26  2020.02  [Refereed]  [International journal]

     View Summary

    Stromal cell-derived factor-2 (SDF-2) is reportedly involved in multiple endoplasmic reticulum (ER) functions, including the misfolded protein catabolic process, protein glycosylation, and ER protein quality control. However, the precise molecular and cellular functions of SDF-2 remain unknown. Previously, we discovered that SDF-2 mediates acquired resistance to oxaliplatin in human gastric cancer cells. In this study, we have generated SDF-2-specific monoclonal antibodies (mAbs), using the rat medial iliac lymph node method, as a tool to explore novel mechanisms of oxaliplatin resistance. The antibodies detected endogenous human SDF-2 in immunoblotting analyses. In addition, immunoprecipitation analyses revealed the availability of these antibodies for human SDF-2. Thus, these mAbs will be available to elucidate molecular and cellular functions of SDF-2 in cancer cells.

    DOI PubMed

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Books and Other Publications 【 display / non-display

Misc 【 display / non-display

  • Sarcolipinヘテロ欠損マウスにおける心房機能解析

    志村 大輔, 草刈 洋一郎, 笹野 哲郎, 中島 康弘, 中井 岳, 焦 其彬, 金 美花, 横田 知大, 石川 義弘, 中野 敦, 合田 亘人, 南沢 享

    日本生理学雑誌   78 ( 3 ) 59 - 59  2016.05

  • マクロファージ特異的HIF‐1α欠損による食餌性肥満マウスの糖代謝・脂肪組織への影響

    TAKIGAWA AKIKO, MAHMOOD ARSHAD, NAWAZ ALLAH, SUMI TOMONOBU, YAMAMOTO SEIJI, TSUNEYAMA KOICHI, OKABE KEISUKE, SENDA SATOKO, NAKAGAWA TAKASHI, USUI ISAO, GODA NOBUHITO, TOBE KAZUYUKI

    糖尿病   58 ( Supplement 1 ) S.447  2015.04

    J-GLOBAL

  • 鳥類の動脈管閉鎖時に弾性線維構造が断裂・減弱する

    赤池 徹, 大森 依里子, 梶村 いちげ, 宮川 幸子, 田, 合田 亘人, 南沢 享

    日本小児循環器学会雑誌   30 ( Suppl. ) s332 - s332  2014.06

  • The manner of metabolism is different between the atrium and the ventricle

    Daisukie Shimura, Qibin Jiao, Kasumi Kashikura, Keiko Endo, Tomoyoshi Soga, Nobuhito Goda, Susumu Minamisawa

    FASEB JOURNAL   26  2012.04

    Research paper, summary (international conference)  

  • HIF-1 in T Cells Ameliorates Intestinal Inflammation by Controlling Regulatory T Cell Homeostasis

    Masaaki Higashiyama, Ryota Hokari, Hideaki Hozumi, Chie Kurihara, Toshihide Ueda, Chikako Watanabe, Kengo Tomita, Mitsuyasu Nakamura, Shunsuke Komoto, Yoshikiyo Okada, Atsushi Kawaguchi, Shigeaki Nagao, Makoto Suematsu, Nobuhito Goda, Soichim Miura

    GASTROENTEROLOGY   140 ( 5 ) S844 - S844  2011.05

    Research paper, summary (international conference)  

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Awards 【 display / non-display

  • Best Poster Award

    2011.10   6th International Symposium on ALPD and Cirrhosis  

    Winner: 合田 亘人

  • 高田賞 第30回アルコール医学生物学研究会

    2010  

  • 上原記念生命科学財団 海外留学助成ポストドクトラルフェローシップ

    2000  

Research Projects 【 display / non-display

  • 肝臓由来のタンパク質を介した臓器間クロストークに基づく新しい血糖調節機構の解明

    基盤研究(C)

    Project Year :

    2020.04
    -
    2023.03
     

    合田 亘人

  • 新規ヘパトカインのニューレグリン1を介した糖尿病の病態制御機構の解明

    基盤研究(C)

    Project Year :

    2017.04
    -
    2020.03
     

    合田 亘人

  • ;The roles of hypoxia signaling in the pathogenesis of lifestyle related diseases

    Grant-in-Aid for Scientific Research on Innovative Areas (Research in a proposed research area)

    Project Year :

    2014.07
    -
    2019.03
     

    Nangaku Masaomi

     View Summary

    Kidney, liver or heart consumes a large amount of molecular oxygen to maintain its activity, thus oxygen availability in each organ could influence its function. The molecular link, however, between hypoxic environment and the disease progression has not been fully elucidated.
    In this study, we examined the roles of hypoxia inducible factor (HIF)-1alpha; signaling during the pathogenesis of lifestyle related diseases including chronic kidney disease, drug-induced liver injury and heart failure. Based on the in vivo animal models, we identified part of the critical pathways which augment the disease progression. In addition, we established a phosphorescence-based technology where we could measure tissue oxygen concentration quantitatively. These results will help us to gain a novel insight into the pathogenesis of lifestyle related disorders.

  • The regulation of in vitro megakaryocyte differentiation and platelet production by hypoxia

    Grant-in-Aid for Young Scientists (B)

    Project Year :

    2013.04
    -
    2015.03
     

    KANAI MAI, GODA Nobuhito, HOUKUWA Kaori, MATHUBARA Yumiko

     View Summary

    The skill of producing platelets in vitro is needed for over tens of thousands of patients with various kinds of platelet disorders. In this study, we aimed to investigate relevance of metabolic systems to megakaryocyte(MK) differentiation and their regulatory mechanism in MK differentiation using preadipocytes isolated from subcutaneous adipose tissues of mice. In MK differentiation, we found characteristic metabolic alterations such as activation of glycolysis, increased cholesterol levels, and enhanced mitochondrial biogenesis. Moreover, hypoxia-inducible factor α (HIFα), a central transcription factor that controls adaptive response to hypoxic stress in normal and pathological conditions, do not affect MK differentiation unlike the regulation of the hematopoietic stem cells.

  • Molecular mechanisms of ductus arteriosus closure

    Grant-in-Aid for Scientific Research (B)

    Project Year :

    2011.04
    -
    2014.03
     

    MINAMISAWA Susumu, YOKOYAMA Utako, GODA Nobuhito, ISHIKAWA Yoshihiro, NAKAMURA Tomoyuki, SUGIMOTO Yukihiko, AOKI Hiroki

     View Summary

    The ductus arteriosus (DA) is an essential fetal artery that closes immediately after birth. However, the molecular mechanisms remain unknown, especially its vascular remodeling. We found that 1) prostaglandin E2 (PGE2) -EP4 signaling decreased elastic fiber formation through degradation of the cross-linking enzyme lysyl oxidase, and that 2) NFkB signal could be activated by PGE2-EP4 stimulation via cAMP-independent pathway, and that 3) endothelial cells of the DA exhibited a unique gene profile involved in the regulation of DA-specific morphology and function. These novel findings regarding DA vascular remodeling could open a possibility to innovate a new therapeutic strategy for the regulation of DA closure.

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Presentations 【 display / non-display

  • 2型糖尿病で肝臓から分泌される Hepatokine X は膵島肥大を誘導することで 血糖調節にかかわっている

    林 絵莉子, 新井 理智, 合田 亘人

    第27回肝細胞研究会 

    Presentation date: 2020.12

    Event date:
    2020.12
     
     
  • 肝臓の代謝・炎症疾患におけるHIF1の病態抑制機構

    合田 亘人  [Invited]

    第72回日本酸化ストレス学会 

    Presentation date: 2019.06

  • 自然免疫様T細胞のHIF-1による急性炎症制御機構の解明

    合田 亘人

    第91回日本生化学会 

    Presentation date: 2018.09

  • 新しい糖新生調節因子の探索とその機能解析

    合田 亘人  [Invited]

    第5回肝臓と糖尿病・代謝研究会 

    Presentation date: 2018.07

  • Pathological role of HIF-1 in the liver

    GODA Nobuhito  [Invited]

    Hypoxia Research Meeting 2018 

    Presentation date: 2018.07

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Specific Research 【 display / non-display

  • 2型糖尿病における肝臓内GPNMB発現制御機構の解明

    2020   林 絵莉子, 鈴木 達也

     View Summary

    当研究室ではこれまでに、Gpnmbが2型糖尿病を発症したマウス肝臓で発現誘導され、かつ糖新生を抑制する内因性抗糖尿病因子であることを見いだしてきた。本研究成果として、Gpnmbの発現が飽和脂肪酸のパルミチン酸(PA)により増加する結果を得た。また、このGpnmb発現誘導にERストレス経路の1つであるPERK経路がかかわることを見いだした。さらに、転写因子C/EBPがPERK経路の下流でPAによるGpnmbの発現誘導にかかわる可能性を見いだした。以上より、2型糖尿病のマウス肝臓で発現誘導されるGpnmbはPAによるPERK-C/EBP経路を介していることが明らかになった

  • GPNMBによる糖代謝制御機能の解明

    2019   大串 悠斗, 田中 大志

     View Summary

    Gpnmb (glycoprotein nonmetastatic melanomaprotein B)は骨大理石病ラットの骨芽細胞で同定された1回膜貫通タンパク質である。本研究では、生体内糖代謝制御における肝臓のGpnmbの役割を解析した。正常マウスの肝臓にGpnmb遺伝子を一過性に発現させると、肝糖新生能の低下を伴った糖処理能力が増強されることが分かった。また、この結果に一致して、糖新生律速酵素のPEPCKやG6Paseの遺伝子およびタンパク質の発現レベルが低下することを見いだした。さらに、初代培養肝細胞を用いて、Gpnmb遺伝子のノックダウンを行った結果、糖新生律速酵素の遺伝子の発現増強と糖産生の増加を見出した。これらの結果より、Gpnmbは肝糖新生を抑制することで血糖を調節する因子であると結論づけた。

  • 新規ヘパトカインのニューレグリン1による糖代謝制御機構の解明

    2016   合田 亘人, 新井 理智, 有村 祐次郎, 大野 友美絵

     View Summary

    本課題では、肝臓で発現する膜貫通型成長因子ニューレグリン1(Nrg1)のバリアントフォームの同定と糖代謝制御における機能について解析を行った。その結果、肝臓ではType1型Nrg1が主に発現していることが分かった。正常マウスにこの遺伝子を強制発現させると糖負荷時の血糖上昇抑制が認められた。この血糖降下はNrg1の糖新生抑制作用によること、切断・分泌されたNrg1の細胞外ドメインが肝細胞自身に働きかけることで発現していることを明らかにした。以上の結果より、肝臓で発現するType1型Nrg1は肝臓局所で作用し肝糖産生能を抑制するヘパトカインであると結論づけた(Arai et al, Sci Rep., 2017)。

  • ニューレグリン1を介した肝臓-膵臓の臓器連関による糖代謝制御機構の解明

    2015   新井 理智, 鈴木 智大, 佐山 慧門, 有村 祐次郎, 大野 友美絵

     View Summary

    別添参照

  • 脂肪蓄積を制御する新しい低酸素ストレス応答の解明

    2015   横野 航太, 山田 祥子, 横関 京介, 田中 裕子, 橋本 昂士郎

     View Summary

    肥満は糖尿病や動脈硬化など健康寿命の延伸を妨げる重篤な疾患の共通した基盤病態である。本研究では、肥満の形成・進展における低酸素の病態生理学的意義を明らかにすることを目指し、ショウジョウバエを用いた遺伝的スクリーニングによる新しい低酸素ストレス関連因子の同定とその機能解析に取り組んだ。その結果、脂肪組織において、低酸素ストレス応答の中心分子HIFの恒常的な活性化により惹起された脂肪蓄積抑制にかかわる遺伝子の同定に成功した。また、3T3-L1細胞を用いた解析から、この遺伝子のマウスオロソログの発現抑制が脂肪蓄積を抑制することも見出した。

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Syllabus 【 display / non-display

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