| Project/Area Number |
17209027
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| Research Category |
Grant-in-Aid for Scientific Research (A)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Gastroenterology
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| Research Institution | Tokyo Medical and Dental University |
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Principal Investigator |
WATANABE Mamoru Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Professor, 大学院医歯学総合研究科, 教授 (10175127)
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| Co-Investigator(Kenkyū-buntansha) |
TSUCHIYA Kiichiro Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Instructor, 大学院医歯学総合研究科, 助手 (40376786)
KIYONO Hiroshi The University of Tokyo, The Institute of Medical Science, Professor, 医科学研究所, 教授 (10271032)
HANDA Hiroshi Tokyo Institute of Technology, Professor, 大学院生命理工学研究科, 教授 (80107432)
垣生 園子 東海大学, 医学部, 教授 (30051618)
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| Project Period (FY) |
2005 – 2006
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| Project Status |
Completed (Fiscal Year 2006)
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| Budget Amount *help |
¥49,920,000 (Direct Cost: ¥38,400,000、Indirect Cost: ¥11,520,000)
Fiscal Year 2006: ¥18,330,000 (Direct Cost: ¥14,100,000、Indirect Cost: ¥4,230,000)
Fiscal Year 2005: ¥31,590,000 (Direct Cost: ¥24,300,000、Indirect Cost: ¥7,290,000)
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| Keywords | Differentiation / Regenerative medicine / Translational research / Signal transduction / Atoh1 / Hath1 / Wnt / Notch / Wntシグナル / Notchシグナル / 細胞内シグナル伝達 / ユビキチン-プロテアソーム / 腸管分化 / 転写因子 / Hath-1 |
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| Research Abstract |
In this study, we revealed the crosstalk between Ant and Notch signaling in the regulation of the intestinal differentiation via Hath1 gene that plays a crucial role in intestinal differentiation.
Atoh1/Hath1 is indispensable to the differentiation of the intestinal epithelial cells, however what regulates Hath1 function has unknown. So we assessed the effect of Ant and Notch signal for Hath1 and then, we revealed new signaling pathway for Hath1 in both signals. Notch signal suppresses the Hath1 mRNA transcription besides increasing HES1 gene expression. Moreover Ant signal degrades Hath1 protein via GSK3 besides stabilizing beta-catenin protein, resulting the differentiation of intestinal epithelial cells.
Next we demonstrated whether the failure of these systems misses Hath1 expression and causes colon disease. In colon cancer, aberrant Ant signal caused the degradation of Hath1 protein in inverse of the stabilization of beta-catenin protein. In ulcerative colitis. Notch signal is aberrantly activated, causing Hath1 gene suppression and goblet cell depletion.
All these data indicate that intestinal differentiation is regulated by Hath1 expression controlled in two distinct points on which Notch signal and Ant signal have effects respectively. Moreover, the failure of these systems causes major colon disease such as cancer or inflammation. Therefore, these new mechanisms may be new targets on the therapy for colon diseases.
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