徳島大学 / 教育研究者総覧 --- 渡邊謙吾

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徳島大学 ⟩ 大学院医歯薬学研究部 ⟩ 医学域 ⟩ 医科学部門 ⟩ 社会医学系 ⟩ メディカルAIデータサイエンス ⟩
徳島大学 ⟩ 医学部 ⟩ 医学科 ⟩ 社会環境医学講座 ⟩ メディカルAIデータサイエンス分野 ⟩

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研究活動

個人のホームページ

https://researchmap.jp/ken5watanabe (researchmap)

https://orcid.org/0000-0002-0348-1634 (ORCID)

専門分野

○	ライフサイエンス (Life sciences) [薬系衛生、生物化学 (Pharmaceuticals - health and biochemistry)]
○	ライフサイエンス (Life sciences) [細胞生物学 (Cell biology)]
○	ライフサイエンス (Life sciences) [機能生物化学 (Functional biochemistry)]
○	ライフサイエンス (Life sciences) [分子生物学 (Molecular biology)]
○	ライフサイエンス (Life sciences) [栄養学、健康科学 (Nutrition and health science)]
○	情報通信 (Informatics) [生命、健康、医療情報学 (Biological, health, and medical informatics)]

研究テーマ

著書・論文

著書:

1.	渡邊謙吾, 一條秀憲 : 液-液相分離による浸透圧感知(BIO Clinica 2023年4月号), 北隆館, 東京, 2023年3月.
2.	渡邊謙吾 : 観察した液滴の画像解析による定量評価(実験医学別冊最強のステップUPシリーズ), 株式会社羊土社, 東京, 2022年7月.
3.	渡邊謙吾, 名黒功, 一條秀憲 : 細胞は浸透圧ストレスを液-液相分離によって細胞内部で感知する(実験医学 2021年7月号), 株式会社羊土社, 東京, 2021年6月.
4.	渡邊謙吾, 名黒功, 一條秀憲 : ハイコンテントゲノムワイドsiRNA スクリーニングによるシグナル伝達研究への応用(実験医学 2014年6月号), 株式会社羊土社, 東京, 2014年5月.

学術論文(審査論文):

1.	Adam R. Burns, Jack Wiedrick, Alicia Feryn, Michal Maes, Mukul K. Midha, David H. Baxter, Seamus R. Morrone, Timothy J. Prokop, Charu Kapil, Michael R. Hoopmann, Ulrike Kusebauch, Eric W. Deutsch, Noa Rappaport, Kengo Watanabe, Robert L. Moritz, Richard A. Miller, Jodi A. Lapidus and Eric S. Orwoll : Proteomic changes induced by longevity-promoting interventions in mice., GeroScience, Vol.46, No.2, 1543-1560, 2024. (要約) Using mouse models and high-throughput proteomics, we conducted an in-depth analysis of the proteome changes induced in response to seven interventions known to increase mouse lifespan. This included two genetic mutations, a growth hormone receptor knockout (GHRKO mice) and a mutation in the Pit-1 locus (Snell dwarf mice), four drug treatments (rapamycin, acarbose, canagliflozin, and 17α-estradiol), and caloric restriction. Each of the interventions studied induced variable changes in the concentrations of proteins across liver, kidney, and gastrocnemius muscle tissue samples, with the strongest responses in the liver and limited concordance in protein responses across tissues. To the extent that these interventions promote longevity through common biological mechanisms, we anticipated that proteins associated with longevity could be identified by characterizing shared responses across all or multiple interventions. Many of the proteome alterations induced by each intervention were distinct, potentially implicating a variety of biological pathways as being related to lifespan extension. While we found no protein that was affected similarly by every intervention, we identified a set of proteins that responded to multiple interventions. These proteins were functionally diverse but tended to be involved in peroxisomal oxidation and metabolism of fatty acids. These results provide candidate proteins and biological mechanisms related to enhancing longevity that can inform research on therapeutic approaches to promote healthy aging. (キーワード) Mice / Animals / Longevity / プロテオーム (proteome) / プロテオミクス (proteomics) / Transcription Factors / Receptors, Somatotropin (出版サイトへのリンク) ● Publication site (DOI): 10.1007/s11357-023-00917-z (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37653270 ● Summary page in Scopus @ Elsevier: 2-s2.0-85169162929 (DOI: 10.1007/s11357-023-00917-z, PubMed: 37653270, Elsevier: Scopus)
2.	Kengo Watanabe, Tomasz Wilmanski, Priyanka Baloni, Max Robinson, Gonzalo G. Garcia, Michael R. Hoopmann, Mukul K. Midha, David H. Baxter, Michal Maes, Seamus R. Morrone, Kelly M. Crebs, Charu Kapil, Ulrike Kusebauch, Jack Wiedrick, Jodi Lapidus, Lance Pflieger, Christopher Lausted, Jared C. Roach, Gwênlyn Glusman, Steven R. Cummings, Nicholas J. Schork, Nathan D. Price, Leroy Hood, Richard A. Miller, Robert L. Moritz and Noa Rappaport : Lifespan-extending interventions induce consistent patterns of fatty acid oxidation in mouse livers, Communications Biology, Vol.6, No.1, 768, 2023. (要約) Aging manifests as progressive deteriorations in homeostasis, requiring systems-level perspectives to investigate the gradual molecular dysregulation of underlying biological processes. Here, we report systemic changes in the molecular regulation of biological processes under multiple lifespan-extending interventions. Differential Rank Conservation (DIRAC) analyses of mouse liver proteomics and transcriptomics data show that mechanistically distinct lifespan-extending interventions (acarbose, 17α-estradiol, rapamycin, and calorie restriction) generally tighten the regulation of biological modules. These tightening patterns are similar across the interventions, particularly in processes such as fatty acid oxidation, immune response, and stress response. Differences in DIRAC patterns between proteins and transcripts highlight specific modules which may be tightened via augmented cap-independent translation. Moreover, the systemic shifts in fatty acid metabolism are supported through integrated analysis of liver transcriptomics data with a mouse genome-scale metabolic model. Our findings highlight the power of systems-level approaches for identifying and characterizing the biological processes involved in aging and longevity. (キーワード) Animals / Mice / Longevity / Lipid Metabolism / 加齢 (aging) / Disease Models, Animal / Liver / Fatty Acids (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s42003-023-05128-y (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37481675 ● Summary page in Scopus @ Elsevier: 2-s2.0-85165420884 (DOI: 10.1038/s42003-023-05128-y, PubMed: 37481675, Elsevier: Scopus)
3.	Kazuhiro Morishita, Kengo Watanabe, Isao Naguro and Hidenori Ichijo : Sodium ion influx regulates liquidity of biomolecular condensates in hyperosmotic stress response, Cell Reports, Vol.42, No.4, 112315, 2023. (要約) Biomolecular condensates are membraneless structures formed through phase separation. Recent studies have demonstrated that the material properties of biomolecular condensates are crucial for their biological functions and pathogenicity. However, the phase maintenance of biomolecular condensates in cells remains elusive. Here, we show that sodium ion (Na+) influx regulates the condensate liquidity under hyperosmotic stress. ASK3 condensates have higher fluidity at the high intracellular Na+ concentration derived from extracellular hyperosmotic solution. Moreover, we identified TRPM4 as a cation channel that allows Na+ influx under hyperosmotic stress. TRPM4 inhibition causes the liquid-to-solid phase transition of ASK3 condensates, leading to impairment of the ASK3 osmoresponse. In addition to ASK3 condensates, intracellular Na+ widely regulates the condensate liquidity and aggregate formation of biomolecules, including DCP1A, TAZ, and polyQ-protein, under hyperosmotic stress. Our findings demonstrate that changes in Na+ contribute to the cellular stress response via liquidity maintenance of biomolecular condensates. (キーワード) Biomolecular Condensates / Ions / Osmoregulation / 相転移 (phase transition) (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.celrep.2023.112315 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37019112 ● Search Scopus @ Elsevier (PMID): 37019112 ● Search Scopus @ Elsevier (DOI): 10.1016/j.celrep.2023.112315 (DOI: 10.1016/j.celrep.2023.112315, PubMed: 37019112)
4.	Kengo Watanabe, Tomasz Wilmanski, Christian Diener, John C. Earls, Anat Zimmer, Briana Lincoln, Jennifer J. Hadlock, Jennifer C. Lovejoy, Sean M. Gibbons, Andrew T. Magis, Leroy Hood, Nathan D. Price and Noa Rappaport : Multiomic signatures of body mass index identify heterogeneous health phenotypes and responses to a lifestyle intervention, Nature Medicine, Vol.29, No.4, 996-1008, 2023. (要約) Multiomic profiling can reveal population heterogeneity for both health and disease states. Obesity drives a myriad of metabolic perturbations and is a risk factor for multiple chronic diseases. Here we report an atlas of cross-sectional and longitudinal changes in 1,111 blood analytes associated with variation in body mass index (BMI), as well as multiomic associations with host polygenic risk scores and gut microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program (Arivale). Machine learning model predictions of BMI from blood multiomics captured heterogeneous phenotypic states of host metabolism and gut microbiome composition better than BMI, which was also validated in an external cohort (TwinsUK). Moreover, longitudinal analyses identified variable BMI trajectories for different omics measures in response to a healthy lifestyle intervention; metabolomics-inferred BMI decreased to a greater extent than actual BMI, whereas proteomics-inferred BMI exhibited greater resistance to change. Our analyses further identified blood analyte-analyte associations that were modified by metabolomics-inferred BMI and partially reversed in individuals with metabolic obesity during the intervention. Taken together, our findings provide a blood atlas of the molecular perturbations associated with changes in obesity status, serving as a resource to quantify metabolic health for predictive and preventive medicine. (キーワード) Humans / Body Mass Index / Cross-Sectional Studies / Multiomics / 肥満症 (obesity) / Phenotype (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s41591-023-02248-0 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 36941332 ● Summary page in Scopus @ Elsevier: 2-s2.0-85150423431 (DOI: 10.1038/s41591-023-02248-0, PubMed: 36941332, Elsevier: Scopus)
5.	Saki Takayanagi, Kengo Watanabe, Takeshi Maruyama, Motoyuki Ogawa, Kazuhiro Morishita, Mayumi Soga, Tomohisa Hatta, Tohru Natsume, Tomoya Hirano, Hiroyuki Kagechika, Kazuki Hattori, Isao Naguro and Hidenori Ichijo : ASKA technology-based pull-down method reveals a suppressive effect of ASK1 on the inflammatory NOD-RIPK2 pathway in brown adipocytes, Scientific Reports, Vol.11, No.1, 22009, 2021. (要約) Recent studies have shown that adipose tissue is an immunological organ. While inflammation in energy-storing white adipose tissues has been the focus of intense research, the regulatory mechanisms of inflammation in heat-producing brown adipose tissues remain largely unknown. We previously identified apoptosis signal-regulating kinase 1 (ASK1) as a critical regulator of brown adipocyte maturation; the PKA-ASK1-p38 axis facilitates uncoupling protein 1 (UCP1) induction cell-autonomously. Here, we show that ASK1 suppresses an innate immune pathway and contributes to maintenance of brown adipocytes. We report a novel chemical pull-down method for endogenous kinases using analog sensitive kinase allele (ASKA) technology and identify an ASK1 interactor in brown adipocytes, receptor-interacting serine/threonine-protein kinase 2 (RIPK2). ASK1 disrupts the RIPK2 signaling complex and inhibits the NOD-RIPK2 pathway to downregulate the production of inflammatory cytokines. As a potential biological significance, an in vitro model for intercellular regulation suggests that ASK1 facilitates the expression of UCP1 through the suppression of inflammatory cytokine production. In parallel to our previous report on the PKA-ASK1-p38 axis, our work raises the possibility of an auxiliary role of ASK1 in brown adipocyte maintenance through neutralizing the thermogenesis-suppressive effect of the NOD-RIPK2 pathway. (キーワード) Adipocytes, Brown / Adipocytes, White / Animals / 細胞質分裂 (cytokinesis) / HEK293 Cells / Humans / 炎症 (inflammation) / MAP Kinase Kinase Kinase 5 / Mice / Nod Signaling Adaptor Proteins / Receptor-Interacting Protein Serine-Threonine Kinase 2 / シグナル伝達 (signal transduction) / Uncoupling Protein 1 (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s41598-021-01123-7 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 34759307 ● Summary page in Scopus @ Elsevier: 2-s2.0-85118850723 (DOI: 10.1038/s41598-021-01123-7, PubMed: 34759307, Elsevier: Scopus)
6.	Kengo Watanabe, Kazuhiro Morishita, Xiangyu Zhou, Shigeru Shiizaki, Yasuo Uchiyama, Masato Koike, Isao Naguro and Hidenori Ichijo : Cells recognize osmotic stress through liquid liquid phase separation lubricated with poly(ADP-ribose), Nature Communications, Vol.12, No.1, 1353, 2021. (要約) Cells are under threat of osmotic perturbation; cell volume maintenance is critical in cerebral edema, inflammation and aging, in which prominent changes in intracellular or extracellular osmolality emerge. After osmotic stress-enforced cell swelling or shrinkage, the cells regulate intracellular osmolality to recover their volume. However, the mechanisms recognizing osmotic stress remain obscured. We previously clarified that apoptosis signal-regulating kinase 3 (ASK3) bidirectionally responds to osmotic stress and regulates cell volume recovery. Here, we show that macromolecular crowding induces liquid-demixing condensates of ASK3 under hyperosmotic stress, which transduce osmosensing signal into ASK3 inactivation. A genome-wide small interfering RNA (siRNA) screen identifies an ASK3 inactivation regulator, nicotinamide phosphoribosyltransferase (NAMPT), related to poly(ADP-ribose) signaling. Furthermore, we clarify that poly(ADP-ribose) keeps ASK3 condensates in the liquid phase and enables ASK3 to become inactivated under hyperosmotic stress. Our findings demonstrate that cells rationally incorporate physicochemical phase separation into their osmosensing systems. (キーワード) Amino Acid Motifs / Amino Acid Sequence / 細胞質分裂 (cytokinesis) / HEK293 Cells / Humans / Lubrication / MAP Kinase Kinase Kinases / Models, Molecular / Mutation / NAD / Nicotinamide Phosphoribosyltransferase / Osmotic Pressure / Phosphoprotein Phosphatases / Poly Adenosine Diphosphate Ribose / Protein Domains (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s41467-021-21614-5 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33649309 ● Summary page in Scopus @ Elsevier: 2-s2.0-85101807116 (DOI: 10.1038/s41467-021-21614-5, PubMed: 33649309, Elsevier: Scopus)
7.	Ryoki Nakamura, Tomohiro Numata, Go Kasuya, Takeshi Yokoyama, Tomohiro Nishizawa, Tsukasa Kusakizako, Takafumi Kato, Tatsuya Hagino, Naoshi Dohmae, Masato Inoue, Kengo Watanabe, Hidenori Ichijo, Masahide Kikkawa, Mikako Shirouzu, Thomas J. Jentsch, Ryuichiro Ishitani, Yasunobu Okada and Osamu Nureki : Cryo-EM structure of the volume-regulated anion channel LRRC8D isoform identifies features important for substrate permeation, Communications Biology, Vol.3, No.1, 240, 2020. (要約) Members of the leucine-rich repeat-containing 8 (LRRC8) protein family, composed of the five LRRC8A-E isoforms, are pore-forming components of the volume-regulated anion channel (VRAC). LRRC8A and at least one of the other LRRC8 isoforms assemble into heteromers to generate VRAC transport activities. Despite the availability of the LRRC8A structures, the structural basis of how LRRC8 isoforms other than LRRC8A contribute to the functional diversity of VRAC has remained elusive. Here, we present the structure of the human LRRC8D isoform, which enables the permeation of organic substrates through VRAC. The LRRC8D homo-hexamer structure displays a two-fold symmetric arrangement, and together with a structure-based electrophysiological analysis, revealed two key features. The pore constriction on the extracellular side is wider than that in the LRRC8A structures, which may explain the increased permeability of organic substrates. Furthermore, an N-terminal helix protrudes into the pore from the intracellular side and may be critical for gating. (キーワード) Cryoelectron Microscopy / Ion Transport / Protein Domains / Protein Isoforms / シグナル伝達 (signal transduction) / Voltage-Dependent Anion Channels (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s42003-020-0951-z (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32415200 ● Summary page in Scopus @ Elsevier: 2-s2.0-85084736903 (DOI: 10.1038/s42003-020-0951-z, PubMed: 32415200, Elsevier: Scopus)
8.	Sho Sugawara, Yusuke Kanamaru, Shiori Sekine, Lila Maekawa, Akinori Takahashi, Tadashi Yamamoto, Kengo Watanabe, Takao Fujisawa, Kazuki Hattori and Hidenori Ichijo : The mitochondrial protein PGAM5 suppresses energy consumption in brown adipocytes by repressing expression of uncoupling protein 1, The Journal of Biological Chemistry, Vol.295, No.17, 5588-5601, 2020. (要約) Accumulating evidence suggests that brown adipose tissue (BAT) is a potential therapeutic target for managing obesity and related diseases. PGAM family member 5, mitochondrial serine/threonine protein phosphatase (PGAM5), is a protein phosphatase that resides in the mitochondria and regulates many biological processes, including cell death, mitophagy, and immune responses. Because BAT is a mitochondria-rich tissue, we have hypothesized that PGAM5 has a physiological function in BAT. We previously reported that PGAM5-knockout (KO) mice are resistant to severe metabolic stress. Importantly, lipid accumulation is suppressed in PGAM5-KO BAT, even under unstressed conditions, raising the possibility that PGAM5 deficiency stimulates lipid consumption. However, the mechanism underlying this observation is undetermined. Here, using an array of biochemical approaches, including quantitative RT-PCR, immunoblotting, and oxygen consumption assays, we show that PGAM5 negatively regulates energy expenditure in brown adipocytes. We found that PGAM5-KO brown adipocytes have an enhanced oxygen consumption rate and increased expression of uncoupling protein 1 (UCP1), a protein that increases energy consumption in the mitochondria. Mechanistically, we found that PGAM5 phosphatase activity and intramembrane cleavage are required for suppression of UCP1 activity. Furthermore, utilizing a genome-wide siRNA screen in HeLa cells to search for regulators of PGAM5 cleavage, we identified a set of candidate genes, including phosphatidylserine decarboxylase (), which catalyzes the formation of phosphatidylethanolamine at the mitochondrial membrane. Taken together, these results indicate that PGAM5 suppresses mitochondrial energy expenditure by down-regulating UCP1 expression in brown adipocytes and that its phosphatase activity and intramembrane cleavage are required for UCP1 suppression. (キーワード) Adipocytes, Brown / Animals / Cells, Cultured / Down-Regulation / エネルギー代謝 (energy metabolism) / HeLa Cells / Humans / 男性 (male) / Mice, Inbred C57BL / ノックアウトマウス (knockout mice) / Mitochondrial Proteins / 酸素消費 (oxygen consumption) / Phosphoprotein Phosphatases / Uncoupling Protein 1 (出版サイトへのリンク) ● Publication site (DOI): 10.1074/jbc.ra119.011508 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 32144202 ● Summary page in Scopus @ Elsevier: 2-s2.0-85083760367 (DOI: 10.1074/jbc.ra119.011508, PubMed: 32144202, Elsevier: Scopus)
9.	Go Kasuya, Takanori Nakane, Takeshi Yokoyama, Yanyan Jia, Masato Inoue, Kengo Watanabe, Ryoki Nakamura, Tomohiro Nishizawa, Tsukasa Kusakizako, Akihisa Tsutsumi, Haruaki Yanagisawa, Naoshi Dohmae, Motoyuki Hattori, Hidenori Ichijo, Zhiqiang Yan, Masahide Kikkawa, Mikako Shirouzu, Ryuichiro Ishitani and Osamu Nureki : Cryo-EM structures of the human volume-regulated anion channel LRRC8, Nature Structural & Molecular Biology, Vol.25, No.9, 797-804, 2018. (要約) Maintenance of cell volume against osmotic change is crucial for proper cell functions. Leucine-rich repeat-containing 8 proteins are anion-selective channels that extrude anions to decrease the cell volume on cellular swelling. Here, we present the structure of human leucine-rich repeat-containing 8A, determined by single-particle cryo-electron microscopy. The structure shows a hexameric assembly, and the transmembrane region features a topology similar to gap junction channels. The LRR region, with 15 leucine-rich repeats, forms a long, twisted arc. The channel pore is located along the central axis and constricted on the extracellular side, where highly conserved polar and charged residues at the tip of the extracellular helix contribute to permeability to anions and other osmolytes. Two structural populations were identified, corresponding to compact and relaxed conformations. Comparing the two conformations suggests that the LRR region is flexible and mobile, with rigid-body motions, which might be implicated in structural transitions on pore opening. (キーワード) Amino Acid Sequence / Cryoelectron Microscopy / Humans / Ion Channel Gating / Membrane Proteins / Protein Conformation / Sequence Homology, Amino Acid (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s41594-018-0109-6 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 30127360 ● Summary page in Scopus @ Elsevier: 2-s2.0-85052597609 (DOI: 10.1038/s41594-018-0109-6, PubMed: 30127360, Elsevier: Scopus)
10.	Kengo Watanabe, Tsuyoshi Umeda, Kuniyoshi Niwa, Isao Naguro and Hidenori Ichijo : A PP6-ASK3 Module Coordinates the Bidirectional Cell Volume Regulation under Osmotic Stress, Cell Reports, Vol.22, No.11, 2809-2817, 2018. (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.celrep.2018.02.045 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 29539411 ● Summary page in Scopus @ Elsevier: 2-s2.0-85043590434 (DOI: 10.1016/j.celrep.2018.02.045, PubMed: 29539411, Elsevier: Scopus)

学術論文(紀要・その他):

1.	Dylan S Ellis, Kengo Watanabe, Tomasz Wilmanski, Michael S Lustgarten, Andres Ardisson V Korat, Gwênlyn Glusman, Jennifer J Hadlock, Oliver Fiehn, Paola Sebastiani, Nathan D Price, Leroy Hood, Andrew T Magis, Simon J Evans, Lance Pflieger, Jennifer C Lovejoy, Sean M Gibbons, Cory C Funk, Priyanka Baloni and Noa Rappaport : APOE Genotype and Biological Age Impact Inter-Omic Associations Related to Bioenergetics, bioRxiv, 2024. (要約) Apolipoprotein E (APOE) modifies human aging; specifically, the epsilon2 and epsilon4 alleles are among the strongest genetic predictors of longevity and Alzheimer's disease (AD) risk, respectively. However, detailed mechanisms for their influence on aging remain unclear. Herein, we analyzed inter-omic, context-dependent association patterns across APOE genotypes, sex, and health axes in 2,229 community-dwelling individuals to test APOE genotypes for variation in metabolites and metabolite-associations tied to a previously-validated metric of biological aging (BA) based on blood biomarkers. Our analysis, supported by validation in an independent cohort, identified top APOE-associated plasma metabolites as diacylglycerols, which were increased in epsilon2-carriers and trended higher in epsilon4-carriers compared to epsilon3-homozygotes, despite the known opposing aging effects of the allele variants. 'Omics association patterns of epsilon2-carriers and increased biological age were also counter-intuitively similar, displaying increased associations between insulin resistance markers and energy-generating pathway metabolites. These results provide an atlas of APOE-related 'omic associations and support the involvement of bioenergetic pathways in mediating the impact of APOE on aging. (出版サイトへのリンク) ● Publication site (DOI): 10.1101/2024.10.17.618322 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 39605362 ● Search Scopus @ Elsevier (PMID): 39605362 ● Search Scopus @ Elsevier (DOI): 10.1101/2024.10.17.618322 (DOI: 10.1101/2024.10.17.618322, PubMed: 39605362)
2.	Kengo Watanabe, Tomasz Wilmanski, Priyanka Baloni, Max Robinson, Oliver Fiehn, Robert Moritz, Richard Miller and Noa Rappaport : MULTIOMIC SYSTEMS ANALYSIS OF LIFESPAN-EXTENDING INTERVENTIONS IN MOUSE TISSUES, Innovation in Aging, Vol.7, No.Supplement_1, 934, 2023. (要約) Aging is associated with dysregulation of molecular, cellular, and physiological processes. Nutritional and pharmacological interventions with different postulated modes of action have been shown to extend lifespan and delay aging-related diseases in model organisms, suggesting the existence of core cellular processes that mediate the effect on lifespan and healthspan. However, these underlying molecular processes remain largely uncharacterized. In this study, we analyzed multiomic tissue-derived data of lifespan-extending interventions in mice including metabolomics and proteomics from the NIA Longevity Consortium and previously reported transcriptomics. We applied three systems techniques, differential rank conservation (DIRAC) analysis, weighted gene co-expression network analysis (WGCNA), and mouse genome-scale metabolic model (GEM) reconstruction, to the mouse liver proteomic and transcriptomic datasets of lifespan-extending interventions (e.g., acarbose, 17α-estradiol, and rapamycin). We found that these interventions generally strengthen the rank conservation of biological processes and shift metabolic fluxes, with fatty acid metabolism emerging as a common process affected by multiple interventions. We then applied these approaches to an expanded experimental data with additional interventions (e.g., canagliflozin) and tissues (e.g., kidney, muscle, and plasma), confirming our results and further observing varied inter-omic and inter-tissue patterns exerted by lifespan-extending interventions. Our findings highlight the potential of integrative systems analysis to elucidate common and unique cellular and physiological changes relating to aging and lifespan-extending interventions, which have translational potential as preventive and prognostic measures to improve human health. (出版サイトへのリンク) ● Publication site (DOI): 10.1093/geroni/igad104.3000 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1093/geroni/igad104.3000 (DOI: 10.1093/geroni/igad104.3000)
3.	Lance Pflieger, Kengo Watanabe, Max Robinson, Gustavo Glusman, Jodi Lapidus, Oliver Fiehn, Robert Moritz and Noa Rappaport : PROSPECTIVE MULTI-OMIC ANALYSIS OF HUMAN LONGEVITY COHORTS IDENTIFIES ANALYTE NETWORKS ASSOCIATED WITH LONGEVITY, Innovation in Aging, Vol.7, No.Supplement_1, 691-692, 2023. (要約) Serum based biomarkers of longevity have long been sought to explain the mechanisms of healthy aging and longevity. Using a 1:3 case cohort design, the Longevity Consortium has produced untargeted mass spectrometry based proteomic and metabolomic datasets from serum of four cohorts with longevity status, defined as those that reached the age corresponding to the 98th percentile of survival using sex specific and birth cohort specific survival percentiles. The cohorts are the Osteoporotic Fractures in Men study, the Study of Osteoporotic Fractures, the Health, Aging, and Body Composition Study, and the Cardiovascular Health Study. In this study, we integrate metabolomics and proteomics using machine learning and system biology approaches to construct multi-omic signatures predictive of longevity and healthy aging. We identify networks enriched for biomarkers previously shown to be associated with longevity such as apolipoproteins, along with novel associations, and we further compare with our findings in a mouse omics LC dataset of molecular changes induced by life-extending interventions. We show substantial differences between male and female longevity networks. The study highlights the effectiveness of using integrative systems biology methods to capture the heterogeneity of underlying molecular aging phenotypes, in order to generate a robust signature of longevity. The identified biomarker signatures may have significant implications for the development of personalized interventions aimed at promoting healthy aging and preventing age-related diseases. (出版サイトへのリンク) ● Publication site (DOI): 10.1093/geroni/igad104.2245 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1093/geroni/igad104.2245 (DOI: 10.1093/geroni/igad104.2245)
4.	Noa Rappaport, Dylan Ellis, Kengo Watanabe, Tomasz Wilmanski, Leroy Hood, Nathan Price, Cory Funk and Priyanka Baloni : BIOLOGICAL AGING AND APOE STATUS REWIRE INTER-OMIC ASSOCIATIONS RELATED TO BIOENERGETICS IN HUMANS, Innovation in Aging, Vol.7, No.Supplement_1, 631-632, 2023. (要約) Apolipoprotein E (APOE) modifies human aging, with the ϵ2 and ϵ4 alleles being among the strongest genetic predictors of longevity and Alzheimer's disease, respectively. However, the mechanisms of APOE's impact on aging and cognition remain largely uncharacterized. In this study, we analyzed inter-omic context-dependent association patterns across APOE genotype, sex, and health in an undiagnosed cohort of 1950 individuals. We hypothesized that APOE genotypes would show variation in energy metabolites tied to previously-validated metrics of 'biological aging', a modifiable health metric based on blood biomarkers. Our analysis identified top APOE-associated metabolites as diacylglycerols, including oleoyl- and linoleoyl-arachidonoyl-glycerols, similarly increased in APOE ϵ2- and ϵ4- carriers compared to ϵ3-homozygotes. Male ϵ2-carriers and biologically-older males displayed a similar increase in associations between insulin resistance and bioenergetic metabolites including pyruvate, glucose, gluconate, and lactate, a trend which was validated in an independent cohort of TwinsUK females. These results provide an atlas of APOE allele-rewired associations and support the involvement of bioenergetic pathways in mediating APOE impact on longevity and AD risk, suggesting targets for enhancing healthspan via lifestyle-modifications or drug-repurposing. (出版サイトへのリンク) ● Publication site (DOI): 10.1093/geroni/igad104.2058 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1093/geroni/igad104.2058 (DOI: 10.1093/geroni/igad104.2058)
5.	Kengo Watanabe, Tomasz Wilmanski, Lance Pflieger, Christian Diener, John Earls, Jennifer Hadlock, Jennifer Lovejoy, Sean Gibbons, Andrew Magis, Leroy Hood, Nathan Price and Noa Rappapor : Characterization of Blood Multiomics-Based Metabolic Health Measure, Obesity, Vol.31, No.S2, 259, 2023. (出版サイトへのリンク) ● Publication site (DOI): 10.1002/oby.23939 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1002/oby.23939 (DOI: 10.1002/oby.23939)
6.	Xiangyu Zhou, Kengo Watanabe, Kazuhiro Morishita, Jun Hamazaki, Shigeo Murata, Isao Naguro and Hidenori Ichijo : Proteasomal regulation of ASK family kinases dictates cell fate under hyperosmotic stress, bioRxiv, 2023. (要約) Summary The proteasome has an essential role in proteostasis maintenance and is critical for cell survival under proteotoxic conditions including hyperosmotic stress. However, it is unknown how proteasome activity is linked to cell survival/death under hyperosmotic stress. We have previously reported that apoptosis signal-regulating kinase 3 (ASK3) contributes to cell survival through its inactivation under hyperosmotic stress. 19S regulatory particle subunits of the proteasome were enriched in the ASK3 inactivator candidates identified through our genome-wide small interfering RNA (siRNA) screen. In this study, we demonstrate that the proteasome regulates ASK3 inactivation through its proteolytic activity. Intriguingly, the proteasome inactivates ASK3 via degradation of not ASK3 per se but another ASK family member ASK1 which activates ASK3 in a kinase activity-dependent manner. Furthermore, the elevated ASK1 level under proteasome inhibition sensitizes cells to hyperosmotic stress. These findings suggest that ASK family maintenance links proteasome capacity to cell fate bifurcation under hyperosmotic stress. (出版サイトへのリンク) ● Publication site (DOI): 10.1101/2023.05.23.541899 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1101/2023.05.23.541899 (DOI: 10.1101/2023.05.23.541899)
7.	Kengo Watanabe, Tomasz Wilmanski, Priyanka Baloni, Max Robinson, Gonzalo G. Garcia, Michael R. Hoopmann, Mukul K. Midha, David H. Baxter, Michal Maes, Seamus R. Morrone, Kelly M. Crebs, Charu Kapil, Ulrike Kusebauch, Jack Wiedrick, Jodi Lapidus, Jennifer C. Lovejoy, Andrew T. Magis, Christopher Lausted, Jared C. Roach, Gustavo Glusman, Steven R. Cummings, Nicholas J. Schork, Nathan D. Price, Leroy Hood, Richard A. Miller, Robert L. Moritz and Noa Rappaport : Systems-level patterns in biological processes are changed under prolongevity interventions and across biological age, medRxiv, 2022. (要約) Aging manifests as progressive deterioration in cellular and systemic homeostasis, requiring systems-level perspectives to understand the gradual molecular dysregulation of underlying biological processes. Here, we report systems-level changes in the molecular regulation of biological processes under multiple lifespan-extending interventions in mice and across age in humans. In mouse cohorts, Differential Rank Conservation (DIRAC) analyses of liver proteomics and transcriptomics show that mechanistically distinct prolongevity interventions tighten the regulation of aging-related biological modules, including fatty acid metabolism and inflammation processes. An integrated analysis of liver transcriptomics with mouse genome-scale metabolic model supports the shifts in fatty acid metabolism. Additionally, the difference in DIRAC patterns between proteins and transcripts suggests biological modules which may be tightly regulated via cap-independent translation. In a human cohort spanning the majority of the adult lifespan, DIRAC analyses of blood proteomics and metabolomics demonstrate that regulation of biological modules does not monotonically loosen with age; instead, the regulatory patterns shift according to both chronological and biological ages. Our findings highlight the power of systems-level approaches to identifying and characterizing the biological processes involved in aging and longevity. (出版サイトへのリンク) ● Publication site (DOI): 10.1101/2022.07.11.22277435 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1101/2022.07.11.22277435 (DOI: 10.1101/2022.07.11.22277435)
8.	Kazuhiro Morishita, Kengo Watanabe, Isao Naguro and Hidenori Ichijo : Sodium ion regulates liquidity of biomolecular condensates in hyperosmotic stress response, bioRxiv, 2022. (要約) Summary Biomolecular condensates are membraneless structures formed through phase separation. Recent studies have demonstrated that the material properties of biomolecular condensates are crucial for their biological functions and pathogenicity. However, the phase maintenance of biomolecular condensates in cells remains elusive. Here, we show that sodium ion (Na<sup>+</sup>) influx regulates the condensate liquidity under hyperosmotic stress. The fluidity of ASK3 condensates increases at the high intracellular Na<sup>+</sup> concentration derived from extracellular hyperosmotic solution. Moreover, we identified TRPM4 as a cation channel that allows Na<sup>+</sup> influx under hyperosmotic stress. TRPM4 inhibition causes the liquid-to-solid phase transition of ASK3 condensates, leading to impairment of the ASK3 osmoresponse. In addition to ASK3 condensates, intracellular Na<sup>+</sup> widely regulates the condensate liquidity and aggregate formation of biomolecules, including DCP1A, TAZ and polyQ-protein, under hyperosmotic stress. Our findings demonstrate that changes in Na<sup>+</sup> contribute to the cellular stress response via liquidity maintenance of biomolecular condensates. (出版サイトへのリンク) ● Publication site (DOI): 10.1101/2022.06.10.495571 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1101/2022.06.10.495571 (DOI: 10.1101/2022.06.10.495571)
9.	Kengo Watanabe, Tomasz Wilmanski, Christian Diener, John C. Earls, Anat Zimmer, Briana Lincoln, Jennifer J. Hadlock, Jennifer C. Lovejoy, Sean M. Gibbons, Andrew T. Magis, Leroy Hood, Nathan D. Price and Noa Rappaport : Multiomic Body Mass Index signatures in blood reveal clinically relevant population heterogeneity and variable responses to a healthy lifestyle intervention, medRxiv, 2022. (要約) Multiomic profiling can reveal population heterogeneity for both health and disease states. Obesity drives a myriad of metabolic perturbations in individuals and is a risk factor for multiple chronic diseases. Here, we report a global atlas of cross-sectional and longitudinal changes in 1,111 blood analytes associated with variation in Body Mass Index (BMI), as well as the multiomic associations with host polygenic risk scores and gut microbiome composition, from a cohort of 1,277 individuals enrolled in a wellness program. Machine learning model predictions of BMI from blood multiomics captured heterogeneous phenotypic states of host metabolism and gut microbiome composition, better than classically-measured BMI. Moreover, longitudinal analyses identified variable BMI trajectories for different omics measures in response to a healthy lifestyle intervention; metabolomics-inferred BMI decreased to a greater extent than actual BMI, while proteomics-inferred BMI exhibited greater resistance to change. Our analyses further revealed blood analyte–analyte associations that were significantly modified by metabolomics-inferred BMI and partially reversed in the metabolically obese population during the intervention. Taken together, our findings provide a blood atlas of the molecular perturbations associated with changes in obesity status, serving as a valuable resource to robustly quantify metabolic health for predictive and preventive medicine. (出版サイトへのリンク) ● Publication site (DOI): 10.1101/2022.01.20.22269601 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1101/2022.01.20.22269601 (DOI: 10.1101/2022.01.20.22269601)
10.	Kengo Watanabe, Kazuhiro Morishita, Xiangyu Zhou, Shigeru Shiizaki, Yasuo Uchiyama, Masato Koike, Isao Naguro and Hidenori Ichijo : Cells recognize osmotic stress through liquid-liquid phase separation lubricated with poly(ADP-ribose), bioRxiv, 2020. (要約) Cells are under threat of osmotic perturbation; and cell volume maintenance is critical in cerebral edema, inflammation and aging, in which prominent changes in intracellular or extracellular osmolality emerge. After osmotic stress-enforced cell swelling or shrinkage, the cells regulate intracellular osmolality to recover their volume. However, the mechanisms recognizing osmotic stress remain obscured. We previously clarified that apoptosis signal-regulating kinase 3 (ASK3) bidirectionally responds to osmotic stress and regulates cell volume recovery. Here, we report that macromolecular crowding induces liquid-demixing condensates of ASK3 under hyperosmotic stress, which transduce osmosensing signal into ASK3 inactivation. A genome-wide small interfering RNA (siRNA) screen identified an ASK3 inactivation regulator, nicotinamide phosphoribosyltransferase (NAMPT), related to poly(ADP-ribose) signaling. Furthermore, we clarify that poly(ADP-ribose) keeps ASK3 condensates in the liquid phase and enables ASK3 to become inactivated under hyperosmotic stress. Our findings demonstrate that cells rationally incorporate physicochemical phase separation into their osmosensing systems. (出版サイトへのリンク) ● Publication site (DOI): 10.1101/2020.04.20.049759 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1101/2020.04.20.049759 (DOI: 10.1101/2020.04.20.049759)
11.	Go Kasuya, Takanori Nakane, Takeshi Yokoyama, Yanyan Jia, Masato Inoue, Kengo Watanabe, Ryoki Nakamura, Tomohiro Nishizawa, Kusakizako Tsukasa, Tsutsumi Akihisa, Haruaki Yanagisawa, Naoshi Dohmae, Motoyuki Hattori, Hidenori Ichijo, Zhiqiang Yan, Masahide Kikkawa, Mikako Shirouzu, Ryuichiro Ishitani and Osamu Nureki : Cryo-EM structure of the volume-regulated anion channel LRRC8, bioRxiv, 2018. (要約) Maintenance of cell volume against osmotic change is crucial for proper cell functions, such as cell proliferation and migration. The leucine-rich repeat-containing 8 (LRRC8) proteins are anion selective channels, and were recently identified as pore components of the volume-regulated anion channels (VRACs), which extrude anions to decrease the cell volume upon cell-swelling. Here, we present the human LRRC8A structure, determined by a single-particle cryo-electron microscopy analysis. The sea anemone-like structure represents a trimer of dimers assembly, rather than a symmetrical hexameric assembly. The four-spanning transmembrane region has a gap junction channel-like membrane topology, while the LRR region containing 15 leucine-rich repeats forms a long twisted arc. The channel pore is along the central axis and constricted on the extracellular side, where the highly conserved polar and charged residues at the tip of the extracellular helix contribute to the anion and other osmolyte permeability. Comparing the two structural populations facilitated the identification of both compact and relaxed conformations, suggesting that the LRR region is flexible and mobile with rigid-body motions, which might be implicated in structural transitions upon pore opening. Overall, our structure provides a framework for understanding the molecular mechanisms of this unique class of ion channels. (出版サイトへのリンク) ● Publication site (DOI): 10.1101/331207 (文献検索サイトへのリンク) ● Search Scopus @ Elsevier (DOI): 10.1101/331207 (DOI: 10.1101/331207)

総説・解説:

1.	Noa Rappapor and Kengo Watanabe : Biological BMI uncovers hidden health risks and is more responsive to lifestyle shifts, Nature Medicine, Vol.29, No.4, 801-802, Apr. 2023. (キーワード) Humans / Body Mass Index / Life Style / Obesity (出版サイトへのリンク) ● Publication site (DOI): 10.1038/s41591-023-02283-x (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 37041385 ● Summary page in Scopus @ Elsevier: 2-s2.0-85153122084 (DOI: 10.1038/s41591-023-02283-x, PubMed: 37041385, Elsevier: Scopus)
2.	Shunya Ishihara, Hidenori Ichijo and Kengo Watanabe : A Novel Lens for Cell Volume Regulation: Liquid Liquid Phase Separation, Cellular Physiology and Biochemistry, Vol.55, No.S1, 135-160, Apr. 2021. (要約) Cells are constantly exposed to the risk of volume perturbation under physiological conditions. The increase or decrease in cell volume accompanies intracellular changes in cell membrane tension, ionic strength/concentration and macromolecular crowding. To avoid deleterious consequences caused by cell volume perturbation, cells have volume recovery systems that regulate osmotic water flow by transporting ions and organic osmolytes across the cell membrane. Thus far, a number of biomolecules have been reported to regulate cell volume. However, the question of how cells sense volume change and modulate volume regulatory systems is not fully understood. Recently, the existence and significance of phaseseparated biomolecular condensates have been revealed in numerous physiological events, including cell volume perturbation. In this review, we summarize the current understanding of cell volume-sensing mechanisms, introduce recent studies on biomolecular condensates induced by cell volume change and discuss how biomolecular condensates contribute to cell volume sensing and cell volume maintenance. In addition to previous studies of biochemistry, molecular biology and cell biology, a phase separation perspective will allow us to understand the complicated volume regulatory systems of cells. (出版サイトへのリンク) ● Publication site (DOI): 10.33594/000000357 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 33877747 ● Summary page in Scopus @ Elsevier: 2-s2.0-85105692822 (DOI: 10.33594/000000357, PubMed: 33877747, Elsevier: Scopus)
3.	Kazuhiro Morishita, Kengo Watanabe and Hidenori Ichijo : Cell volume regulation in cancer cell migration driven by osmotic water flow, Cancer Science, Vol.110, No.8, 2337-2347, May 2019. (出版サイトへのリンク) ● Publication site (DOI): 10.1111/cas.14079 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 31120184 ● Summary page in Scopus @ Elsevier: 2-s2.0-85068384441 (DOI: 10.1111/cas.14079, PubMed: 31120184, Elsevier: Scopus)
4.	Takuto Nishida, Kazuki Hattori and Kengo Watanabe : The regulatory and signaling mechanisms of the ASK family, Advances in Biological Regulation, Vol.66, 2-22, Dec. 2017. (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.jbior.2017.05.004 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 28669716 ● Summary page in Scopus @ Elsevier: 2-s2.0-85021371885 (DOI: 10.1016/j.jbior.2017.05.004, PubMed: 28669716, Elsevier: Scopus)
5.	Xiangyu Zhou, Isao Naguro, Hidenori Ichijo and Kengo Watanabe : Mitogen-activated protein kinases as key players in osmotic stress signaling, Biochimica et Biophysica Acta (BBA) - General Subjects, Vol.1860, No.9, 2037-2052, Sep. 2016. (出版サイトへのリンク) ● Publication site (DOI): 10.1016/j.bbagen.2016.05.032 (文献検索サイトへのリンク) ● PubMed @ National Institutes of Health, US National Library of Medicine (PMID): 27261090 ● Summary page in Scopus @ Elsevier: 2-s2.0-84976525679 (DOI: 10.1016/j.bbagen.2016.05.032, PubMed: 27261090, Elsevier: Scopus)

国内講演発表:

1.	渡邊謙吾 : 液-液相分離による浸透圧ストレス感知機構, 第97回日本生化学大会(2024年度奨励賞受賞講演 SK1-05), 2024年11月.
2.	渡邊謙吾, 名黒功, 一條秀憲 : 相分離が高浸透圧ストレス下でのPP6によるASK3不活性化を制御する, 第92回日本生化学会大会(シンポジウム 2S09m), 2019年9月.
3.	渡邊謙吾 : ASK3と細胞体積制御:細胞の浸透圧ストレス応答と細胞死誘導における共通機構, 若手研究者が拓く最先端医科学研究(東京大学医科学研究所国際共同利用・共同研究拠点事業), 2019年1月.
4.	渡邊謙吾, 名黒功, 一條秀憲 : PP6-ASK3モジュールは浸透圧ストレス応答の重要な変換器である, 2017年度生命科学系学会合同年次大会(ConBio2017, ワークショップ 2PW15), 2017年12月.

その他・研究会:

1.	渡邊謙吾 : 生命科学研究における大航海時代の幕開け, 領域セミナー(奈良先端科学技術大学院大学バイオサイエンス領域), 2024年8月.
2.	渡邊謙吾 : 健康科学研究における大航海時代の幕開け, 共創の場形成支援プログラム世界モデルとなる自律成長型人材・技術を育む総合健康産業都市拠点「第32 回若手人材育成セミナー」, 2024年4月.
3.	渡邊謙吾 : Beyond the Scale with Biological BMI: Integrated Multiomic Measures of Metabolic Health, 尾池研究室セミナー(熊本大学), 2023年12月.
4.	渡邊謙吾 : ストレス応答研究における大航海時代の幕開け, Nex-Gen Symposium on Cell Signaling, 2023年8月.
5.	Kengo Watanabe : Beyond the Scale with Biological BMI: Integrated Multiomic Measures of Metabolic Health, RIKEN BDR seminar, Aug. 2023.
6.	Kengo Watanabe : Beyond the Scale with Biological BMI: Integrated Multiomic Measures of Metabolic Health, Long Lab seminar (Vanderbilt University Medical Center), Jul. 2023.
7.	渡邊謙吾 : ポリADPリボースは液–液相分離を介して浸透圧応答キナーゼASK3を制御する, 跡見・清水研究室セミナー(東京農工大学), 2019年11月.

特許:

1.	Noa Rappapor, Kengo Watanabe, Tomasz Wilmanski and Nathan Price : OMICS-INFERRED BODY INDEX METHOD AND SYSTEM, 63/480,814 (Jan. 2023), US-20240249847-A1 (Jul. 2024), .

科学研究費補助金 (KAKEN Grants Database @ NII.ac.jp)

細胞の浸透圧ストレス応答機構と細胞死誘導機構における共通原理の探究 (研究課題/領域番号: 19K16067 )
高浸透圧依存的非選択性カチオンチャネルの網羅的探索および同定 (研究課題/領域番号: 17K15086 )
研究者番号（20781727）による検索