Identification of the Notch signal in intestinal epithelial cells and the failure of the intestinal differentiation in chronic colitis.
| Project/Area Number |
17590624
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| Research Category |
Grant-in-Aid for Scientific Research (C)
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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 |
OKADA Eriko Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Fellow, 医学部附属病院, 医員 (20376784)
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| Co-Investigator(Kenkyū-buntansha) |
KUBOTA Daisuke Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Fellow, 医学部附属病院, 医員 (00376790)
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)
WATANABE Mamoru Tokyo Medical and Dental University, Department of Gastroenterology and Hepatology, Professor (10175127)
大島 茂 東京医科歯科大学, 医学部附属病院, 医員 (50376787)
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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 |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2006: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2005: ¥2,200,000 (Direct Cost: ¥2,200,000)
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| Keywords | Notch / Chronic colitis / Regeneration / Stem Cell / Notchシグナル / 腸管分化 / 転写因子 |
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| Research Abstract |
In this study, we demonstrated that Notch signaling plays a crucial role in the differentiation of intestinal epithelial cells, and then we revealed several genes directly targeted by Notch signal in intestinal epithelial cells.
It has been reported that the deficient of HES1 gene via Notch signaling caused the differentiation of intestinal epithelial cells, indicating that Notch signaling regulates the dedifferentiation of intestinal epithelial cells. However the function of Notch signaling has been unknown. Therefore, we aimed to elucidate the effect of Notch signaling in intestinal epithelial cells. First, we established the system of Notch signal stimulation, using the expression of Notch intracellular domain (NICD) induced by doxycycline. Moreover, we established the system of Notch signal inhibition, using γ-secretase inhibitor that suppresses the separation of NICD. The expression of NICD caused the dedifferentiation of intestinal epithelial cells such as the decrease of Mucin2 gene and Hath1 gene, on the contrary, the inhibition of Notch signal caused the differentiation with the increase of Mucin2 gene and Hath1 gene. Therefore, we identified several genes directly targeted by Notch signal stimulation, using RNA micro array analysis for the clarification of Notch function in intestine.
Because Notch signal regulates the differentiation of intestinal cell line, we examined the expression of NICD in human intestine and human colitis. NICD was expressed at the lower crypt, whereas Hes1 and Ki-67 were expressed. Moreover, in intestine of IBD patient, NICD was expressed at higher crypt than in normal intestine, suggesting that the increase of Notch signal suppress the differentiation of the intestinal epithelial cells in IBD. So we assessed the effect of γ-secretase inhibitor on intestinal epithelial cells. The inhibition of Notch signal caused the increase of goblet cells in mouse, indicating that Notch signal may be new target for the therapy of IBD.
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Report
(3 results)
Research Products
(11 results)
