| Project/Area Number |
15K08418
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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| Allocation Type | Multi-year Fund |
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| Section | 一般 |
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| Research Field |
Experimental pathology
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| Research Institution | University of the Ryukyus (2018)
The University of Tokyo (2015-2017) |
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Principal Investigator |
Ichise Taeko 琉球大学, 医学部, 委託非常勤講師 (00396863)
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| Co-Investigator(Kenkyū-buntansha) |
市瀬 広武 琉球大学, 医学部, 准教授 (10313090)
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| Project Period (FY) |
2015-04-01 – 2019-03-31
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| Project Status |
Completed (Fiscal Year 2018)
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| Budget Amount *help |
¥4,940,000 (Direct Cost: ¥3,800,000、Indirect Cost: ¥1,140,000)
Fiscal Year 2017: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000)
Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
Fiscal Year 2015: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
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| Keywords | Ras / MAPキナーゼ経路 / PI3キナーゼ経路 / RalGEF経路 / ケラチノサイト / CBP/p300 |
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| Outline of Final Research Achievements |
To determine how Ras effector pathways contribute to hair and skin development, we generated and utilized transgenic mouse models expressing H-Ras mutants after Cre recombination. We utilized effector mutant Ras proteins, each of which retains binding to a particular type of downstream effector proteins but not to others. H-RasT35S, H-RasE37G and H-RasY40C can activate Raf, RalGDS and PI-3 kinase, respectively. The three mouse lines overexpressing the effector mutants in the epidermis could survive to adulthood and showed different phenotypes of epidermal keratinocytes. Epidermis-specific H-RasT35S-overexpressing mice showed significant thickening of both Krt5 (K5)-positive basal and Krt1 (K1)-positive suprabasal layers during postnatal development. This indicates that overexpressed H-RasS35 increases Ras-Erk signaling in epidermal keratinocytes, leading to Erk-dependent hyperproliferation of keratinocytes.
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| Academic Significance and Societal Importance of the Research Achievements |
本研究において見出した、特定のRas下流シグナルが亢進している遺伝子導入マウスに認められる皮膚や体毛の異常は、RASシグナル関連遺伝子の変異によって引き起こされる、RASopathiesの患者に認められる特徴と類似している。本研究による知見は、形態形成におけるRas下流シグナルの意義を明らかにするのみならず、RASopathiesの新たな治療法の確立および遺伝子変異探索指針の策定にも貢献できると考えられる。また、発毛・育毛や表皮の恒常性維持など、QOLに関わる医学領域の発展にも寄与する成果である。
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