| Project/Area Number |
16K10155
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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 |
Dermatology
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| Research Institution | Osaka University |
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Principal Investigator |
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| Project Period (FY) |
2016-04-01 – 2020-03-31
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| Project Status |
Completed (Fiscal Year 2019)
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| Budget Amount *help |
¥4,680,000 (Direct Cost: ¥3,600,000、Indirect Cost: ¥1,080,000)
Fiscal Year 2018: ¥2,210,000 (Direct Cost: ¥1,700,000、Indirect Cost: ¥510,000)
Fiscal Year 2017: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000)
Fiscal Year 2016: ¥1,040,000 (Direct Cost: ¥800,000、Indirect Cost: ¥240,000)
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| Keywords | mTORC1 / Ca2+チャネル / 結節性硬化症 / 精神神経症状 / 皮膚症状 / 発汗 / 白斑 / カルシウムチャネル / 中枢神経症状 / てんかん / 温痛覚 / Calcium influx / Thermal hypersensitivity / TSC / sirolimus / カルシウムイオン / ホスホイノシトール３リン酸 / 痛覚 / 認知障害・自閉症 / 痛み / イノシトール３リン酸 / mTOR |
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| Outline of Final Research Achievements |
Tuberous sclerosis complex (TSC) is an autosomal dominant inherited disease that causes various lesions in the central nervous system and skin due to the constitutive activation of mammalian/ mechanistic target of rapamycin complex1 (mTORC1). We hypothesized that abnormality of Ca2+ channels mediated by inositol triphosphate (IP3) receptor, which is detected in almost all the cells, might be a common pathological mechanism in the skin and central nervous system of TSC patients. Using the TSC model mice with epilepsy, behavioral abnormalities, vitiligo and abnormal sweating and pain, we investigated a novel mTORC1 mechanism regulating Ca2+ channel and elucidated not only Ca2+ concentration abnormalities but also increased mitochondrial oxidative stress in melanocytes and neurons of model mice. These abnormalities were improved by the administration of sirolimus, mTORC1 inhibitor.
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| Academic Significance and Societal Importance of the Research Achievements |
自閉症や認知障害、てんかん等の精神神経症状と発汗異常、痛覚異常、白斑等の皮膚症状の共通の病態が解明できれば、直接見て触れられ、サンプル採取も容易な皮膚の汗腺細胞や色素細胞で中枢神経の異常が検討でき、研究の発展が望める。更に本機序はTSC以外の多汗症や、てんかん、認知障害、自閉症における新規の病態の解明につながり、治療法のないこれら疾患に新規治療法の提供も可能になり、基礎臨床を問わず本研究の意義は高い。
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