Molecular pharmacological analysis of skin barrier regulatory mechanisms
Project/Area Number |
17H01531
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Research Category |
Grant-in-Aid for Scientific Research (A)
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Allocation Type | Single-year Grants |
Section | 一般 |
Research Field |
General pharmacology
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Research Institution | Kyoto University |
Principal Investigator |
narumiya shuh 京都大学, 医学研究科, 寄附講座教員 (70144350)
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Project Period (FY) |
2017-04-01 – 2020-03-31
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Project Status |
Completed (Fiscal Year 2019)
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Budget Amount *help |
¥41,730,000 (Direct Cost: ¥32,100,000、Indirect Cost: ¥9,630,000)
Fiscal Year 2019: ¥11,310,000 (Direct Cost: ¥8,700,000、Indirect Cost: ¥2,610,000)
Fiscal Year 2018: ¥13,650,000 (Direct Cost: ¥10,500,000、Indirect Cost: ¥3,150,000)
Fiscal Year 2017: ¥16,770,000 (Direct Cost: ¥12,900,000、Indirect Cost: ¥3,870,000)
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Keywords | 皮膚バリアー / アトピー性皮膚炎 / 角化細胞 / フィラグリン / lysophosphatidic acid / Rhoシグナル / アリルハイドロカーボン受容体 / 創傷治癒 / LPA / Aryl Hydorcarbon受容体 / single cell RNA sequencing / 核内受容体 / 転写因子ネットワーク / アトピー / Aryl Hydrocarbon受容体 / 炎症 / 免疫 / 皮膚バリアー機能 / NHEK細胞 / リゾフォスファチジン酸(LPA) / Rho / ROCK / SRF |
Outline of Final Research Achievements |
The skin barrier protects the body from water loss, allergens and pathogens. In this study, we used cultured normal human epidermal keratinocytes, and screened compounds for promotion of skin barrier with induction of a skin barrier protein, filaggrin (FLG) as a parameter. We then extended these in vitro findings to in vivo models. We found, ① lysophosphatidic acid (LPA) acts on its receptors, LPAR1 and LPAR5, to mobilize G12/13-Rho-ROCK-SRF pathway, and promote skin barrier function through keratinocyte maturation, and ② LPA, in addition, induces differentiation of keratinocyte into a separate population involved in skin wound healing. We further found, ③ a class of compounds that induce keratinocyte maturation for barrier function through acting aryl hydrocarbon receptor (AhR), but, unlike conventional AhR ligands such as FICZ and TCDD, are weak or negligible in classic AhR ligand activity such as CYP1A1 induction and apparently without proinflammatory activity.
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Academic Significance and Societal Importance of the Research Achievements |
本研究は、皮膚バリアーの調節機序としてLPA-Rho 経路と新規のAhR経路を同定したことに意義がある。Rho経路は物理的刺激に伴う表皮形成のシグナルとして提唱されてきており、今回の発見は表皮分化について統一的な理解を促進する。また、AhRは、コールタールの皮膚外用薬としての標的であるが、dioxin受容体でもあり、その活性化は一方で皮膚炎症を起こすなど潜在的な毒性のため治療標的としては敬遠されている。本研究で、既存のAhRリガンド活性や炎症惹起を伴わず、皮膚バリアーを亢進する一群の化合物が発見されたことは、AhR研究に新規の視点を導入しその作用の選択的応用に途を拓くものと言える
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Report
(4 results)
Research Products
(41 results)
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[Journal Article] mDia1/3-dependent actin polymerization spatiotemporally controls LAT phosphorylation by Zap70 at the immune synapse.2020
Author(s)
Thumkeo, D., Katsura, Y., Nishimura, Y., Kanchanawong, P., Tohyama, K., Ishizaki, T., Kitajima, S., Takahashi, C., Hirata, T., Watanabe, N., Krummel, M. F., and Narumiya, S.
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Journal Title
Sci. Adv.
Volume: 6
Issue: 1
Pages: 2432-2432
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] LPA Induces Keratinocyte Differentiation and Promotes Skin Barrier Function through the LPAR1/LPAR5-RHO-ROCK-SRF Axis.2018
Author(s)
Sumitomo A, Siriwach R, Thumkeo D, Ito K, Nakagawa R, Tanaka N, Tanabe K, Watanabe A, Kishibe M, Ishida-Yamamoto A, Honda T, Kabashima K, Aoki J, Narumiya S.
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Journal Title
J Invest Dermatol. 2018 Nov 14.
Volume: pii: S0022-202X(18)32815-X.
Issue: 5
Pages: 1010-1022
DOI
NAID
Related Report
Peer Reviewed / Open Access
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[Journal Article] mDia1/3 generate cortical F-actin meshwork in Sertoli cells that is continuous with contractile F-actin bundles and indispensable for spermatogenesis and male fertility.2018
Author(s)
S. Sakamoto, D. Thumkeo, H. Ohta, Z. Zhang, S.R. Huang, P. Kanchenawong, T. Fuu, S. Watanabe, K. Shimada, Y. Fujihara, S. Yoshida, M. Ikawa, N. Watanabe, M. Saitou and S. Narumiya
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Journal Title
Plos Biology
Volume: 16
Issue: 9
Pages: e2004874-e2004874
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Thromboxane A2 facilitates IL-17A production from Vγ4+ γδ T cells and promotes psoriatic dermatitis in mice.2018
Author(s)
Ueharaguchi Y, Honda T, Kusuba N, Hanakawa S, Adachi A, Sawada Y, Otsuka A, Kitoh A, Dainich T, Egawa G, Nakachima C, Nakajima S, Murata T, Ono S, Arita M, Narumiya S, Miyachi Y, Kabashima K
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Journal Title
Journal of Allergy and Clinical Immunology
Volume: in press
Issue: 2
Pages: 680-683.e2
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Inhibition of microsomal prostaglandin E synthase-1 facilitates liver repair after hepatic injury in mice.2018
Author(s)
Nishizawa N, Ito Y, Eshima K, Ohkubo H, Kojo K, Inoue T, Raouf J, Jakobsson PJ, Uematsu S, Akira S, Narumiya S, Watanabe M, Majima M.
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Journal Title
J Hepatol.
Volume: S0168-8278(18)
Issue: 1
Pages: 30126-30130
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Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Dopamine D1 receptor subtype mediates acute stress-induced dendritic growth in excitatory neurons of the medial prefrontal cortex and contributes to suppression of stress susceptibility in mice2017
Author(s)
Shinohara R, Taniguchi M, Ehrlich AT, Yokogawa K, Deguchi Y, Cherasse Y, Lazarus M, Urade Y, Ogawa A, Kitaoka S, Sawa A, Narumiya S, *Furuyashiki T.
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Journal Title
Mol Psychiatry
Volume: -
Issue: 8
Pages: 1717-1730
DOI
NAID
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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[Journal Article] Gut microbiota promotes obesity-associated liver cancer through PGE2-mediated suppression of antitumor immunity.2017
Author(s)
Loo TM, Kamachi F, Watanabe Y, Yoshimoto S, Kanda H, Arai Y, Nakajima-Takagi Y, Iwama A, Koga T, Sugimoto Y, Ozawa T, Nakamura M, Kumagai M, Watashi K, Taketo M, Aoki T, Narumiya S, Oshima M, Arita M, Hara E, Ohtani N.
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Journal Title
Cancer Discov
Volume: in press
Issue: 5
Pages: 522-538
DOI
Related Report
Peer Reviewed / Open Access / Int'l Joint Research
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