慶應義塾研究者情報データベース

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• 2011年04月

  -

  2016年03月

  京都大学医学研究科, 特定准教授

• 2016年04月

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  2017年03月

  慶應義塾大学医学部, 薬理学, 講師

• 2017年04月

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  継続中

  慶應義塾大学医学部, 薬理学, 准教授

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• 薬剤師

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• TRPV4 mediates low-humidity responses in epidermal keratinocytes.

  Tanaka M, Chikuma S, Hara-Chikuma M

  Proceedings of the National Academy of Sciences of the United States of America 123 （ 38 ） e2603334123 2026年09月

  最終著者, 責任著者,  ISSN  0027-8424

  　概要を見る

  Environmental humidity is a key determinant of organismal physiology and homeostasis. Although the genetic basis of humidity-driven responses is well established in invertebrates, the molecular and genetic mechanisms by which mammals respond to low humidity remain unclear. Here, using reconstructed 3D epidermal equivalents and a mouse model, we identify transient receptor potential vanilloid 4 (TRPV4) as an important mediator of low-humidity-induced signaling and transcriptional responses in epidermal keratinocytes. In 3D skin models, low-humidity exposure induced rapid water movement, characterized by enhanced apical water loss and concomitant basal-side water uptake within 90 s, followed by TRPV4-dependent Ca2+ influx within 3 min. Pharmacological TRPV4 inhibition suppressed MAPK activation at 30 min and both early (3 h) and late (24 h) low-humidity-induced transcriptional changes. Ca2+ chelation reduced low-humidity-induced ERK and p38 activation, and ERK inhibition attenuated low-humidity-induced gene expression changes at 3 h. In vivo, acute low-humidity exposure in mice elicited epidermal MAPK activation within 15 min and early transcriptional changes at 3 h, with RNA-sequencing analysis showing enrichment of gene sets associated with cell adhesion or inflammatory responses. These signaling and transcriptomic responses were attenuated in the epidermis of keratinocyte-specific Trpv4 conditional knockout mice. Collectively, our findings identify TRPV4 as an important mediator of epidermalresponses to low-humidity stress, providing a molecular basis for low-humidity-driven signaling in the mammalian epidermis.

  • Access to Document (DOI)

• Glycerol enhances mitochondrial metabolism and inflammatory response in pro-inflammatory macrophages.

  Tanaka M, Hishiki T, Matsuura T, Yasui M, Chikuma S, Hara-Chikuma M

  EMBO reports 27 （ 10 ） 2614 - 2638 2026年04月

  最終著者, 責任著者,  ISSN  1469-221X

  　概要を見る

  Although glycerol is a ubiquitous metabolite in mammalian systems, its cellular metabolic pathways and functions have not been fully elucidated. Here, we find that elevated extracellular glycerol modulates intracellular metabolism and pro-inflammatory responses of macrophages. In pro-inflammatory macrophages stimulated with lipopolysaccharide, glycerol is taken up through glycerol channels including Aquaporin 3 (AQP3) and metabolized to glycerol-3-phosphate (G3P), which is then converted to dihydroxyacetone phosphate by glycerol-3-phosphate dehydrogenase 2 (GPD2). This glycerol-driven pathway enhances mitochondrial ATP production, potentially by supplying electrons to the electron transport chain (ETC) via GPD2, and by upregulating the transcription of genes encoding ETC complexes. In addition, glycerol supplementation elevates intracellular acetyl-CoA levels, promotes histone acetylation at the promoters of pro-inflammatory cytokine genes, and consequently increases cytokine gene expression, suggesting enhanced pro-inflammatory response. In vivo experiments, macrophage-specific AQP3 conditional knockout mice exhibit reduced weight gain and adipose tissue inflammation in a high-fat diet-induced obesity model. Our findings provide novel insights into the metabolic regulation and macrophage inflammation by extracellular glycerol.

  • Access to Document (DOI)

• Aquaporin 3 inhibition attenuates imiquimod-induced psoriatic symptoms in a murine model.

  Okubo R, Tanaka M, Kubo A, Yasui M, Hara-Chikuma M

  Molecular biology reports 52 （ 1 ） 354 - 354 2025年04月

  最終著者, 責任著者,  ISSN  0301-4851

  　概要を見る

  BACKGROUND: Aquaporin 3 (AQP3) is highly expressed in both keratinocytes and T cells within psoriatic skin. Previous studies have demonstrated that AQP3 knockout mice show reduced development of psoriatic symptoms in murine models. This study aims to evaluate the effect of AQP3 inhibition on psoriasis progression. METHODS AND RESULTS: AQP3 conditional knockout mice were generated to assess the role of AQP3 expression in keratinocytes and T cells in psoriasis pathogenesis. In an imiquimod (IMQ)-induced psoriasis model, psoriatic symptoms were significantly reduced in mice with keratinocyte-specific AQP3 deletion. Additionally, AQP3 inhibition by administration of anti-AQP3 monoclonal antibody (mAb) effectively alleviated IMQ-induced psoriasis symptoms in wild-type mice. CONCLUSIONS: AQP3 inhibition presents a promising approach for the treatment of psoriasis.

  • Access to Document (DOI)

• HSP90 promotes tumor associated macrophage differentiation during triple-negative breast cancer progression.

  Hong L, Tanaka M, Yasui M, Hara-Chikuma M

  Scientific reports 14 （ 1 ） 22541 - 22541 2024年09月

  最終著者, 責任著者

  　概要を見る

  Tumor-associated macrophages (TAMs) originating from monocytes are crucial for cancer progression; however, the mechanism of TAM differentiation is unclear. We investigated factors involved in the differentiation of monocytes into TAMs within the tumor microenvironment of triple-negative breast cancer (TNBC). We screened 172 compounds and found that a heat shock protein 90 (HSP90) inhibitor blocked TNBC-induced monocyte-to-TAM differentiation in human monocytes THP-1. TNBC-derived conditional medium (CM) activated cell signaling pathways, including MAP kinase, AKT and STAT3, and increased the expression of TAM-related genes and proteins. These inductions were suppressed by HSP90 inhibition or by knockdown of HSP90 in TNBC. Additionally, we confirmed that TNBC secreted HSP90 extracellularly and that HSP90 itself promoted TAM differentiation. In a mouse tumor model, treatment with an HSP90 inhibitor suppressed tumor growth and reduced TAMs in the tumor microenvironment. Our findings demonstrate the role of HSP90 in TAM differentiation, suggesting HSP90 as a potential target for TNBC immunotherapy due to its regulatory role in monocyte-to-TAM differentiation.

  • Access to Document (DOI)

• Sufficient water intake maintains the gut microbiota and immune homeostasis and promotes pathogen elimination.

  Sato K, Hara-Chikuma M, Yasui M, Inoue J, Kim YG

  iScience 27 （ 6 ） 109903 - 109903 2024年06月

  査読有り

  　概要を見る

  Water is the most abundant substance in the human body and plays a pivotal role in various bodily functions. While underhydration is associated with the incidence of certain diseases, the specific role of water in gut function remains largely unexplored. Here, we show that water restriction disrupts gut homeostasis, which is accompanied by a bloom of gut microbes and decreased numbers of immune cells, especially Th17 cells, within the colon. These microbial and immunological changes in the gut are associated with an impaired ability to eliminate the enteric pathogen Citrobacter rodentium. Moreover, aquaporin 3, a water channel protein, is required for the maintenance of Th17 cell function and differentiation. Taken together, adequate water intake is critical for maintaining bacterial and immunological homeostasis in the gut, thereby enhancing host defenses against enteric pathogens.

  • Access to Document (DOI)

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• AQP3 expression in keratinocytes is involved in hyperplasia in atopic dermatitis

  Kyoko Nakahigashi, Kenji Kabashima, Akihiko Ikoma, Yoshiki Miyachi, Mariko Hara-Chikuma

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 130   S23 - S23 2010年09月

  ISSN  0022-202X

• A controlled aquaporin-3 expression in T lymphocytes regulate their migration and trafficking in cutaneous immune reaction

  M. Hara-Chikuma, S. Chikuma, K. Kabashima, K. Nakahigashi, A. Kamegawa, Y. Fujiyoshi, A. S. Verkman, Y. Sugiyama, S. Inoue, Y. Miyachi

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 130   S116 - S116 2010年04月

  ISSN  0022-202X

• Flaky tail mouse as a possible model of atopic dermatitis

  C. Moniaga, M. Chikuma, H. Kawasaki, S. Nakajima, H. Tanizaki, G. Egawa, T. Honda, M. Amagai, Y. Miyachi, K. Kabashima

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 129   S56 - S56 2009年09月

  ISSN  0022-202X

• FLAKY TAIL MOUSE AS A POSSIBLE MODEL OF ATOPIC DERMATITIS: PRURITUS-ASSOCIATED RESPONSE INDUCED IN FLAKY TAIL MOUSE

  Catharina Sagita Moniaga, Gyohei Egawa, Hiroshi Kawasaki, Mariko Hara Chikuma, Tetsuya Honda, Hideaki Tanizaki, Saeko Nakajima, Yoshiki Tokura, Yoshiki Miyachi, Masayuki Amagai, Kenji Kabashima

  ACTA DERMATO-VENEREOLOGICA 89 （ 6 ） 695 - 695 2009年

  ISSN  0001-5555

• A GPI anchor is required for the epidermal permeability barrier

  S Inoue, M Hara, J Takeda, M Tarutani, Y Uchida, P Elias, W Holleran

  JOURNAL OF INVESTIGATIVE DERMATOLOGY 117 （ 2 ） 415 - 415 2001年08月

  ISSN  0022-202X

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• 低湿度ストレスが関与する皮膚病態制御メカニズムの解明と治療戦略の探索

  2024年04月

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  2027年03月

  竹馬 真理子, 基盤研究(B), 補助金,  研究代表者

• アクアポリン３が制御するがん悪性化の分子機構解明

  2021年04月

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  2024年03月

  文部科学省・日本学術振興会, 科学研究費助成事業, 竹馬 真理子, 基盤研究(C), 補助金,  研究代表者

• アクアポリンが透過するH2O2による皮膚の炎症形成機構の解明

  2016年04月

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  2018年03月

  文部科学省・日本学術振興会, 科学研究費助成事業, 竹馬　真理子, 基盤研究(C), 補助金,  研究代表者

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• 薬理学

  2026年度

• 薬理学

  2025年度

• 薬理学

  2024年度

• 薬理学

  2023年度

• 薬理学

  2022年度

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• 薬理学

  慶應義塾大学

  2016年04月

  -

  継続中

  , 

  学部専門科目, 演習