2001 Fiscal Year Final Research Report Summary
ROLF OF PPAR IN GUT INJURY-ANALYSIS IN ANYMALMODELS
| Project/Area Number |
12670460
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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 | The University of Tokyo |
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Principal Investigator |
MATSUHASHI Nobuyuki THE UNIVERSITY OF TOKYO, FACULTY OF MEDICINE, ASSISTANT PROFESSOR, 医学部・附属病院, 助手 (10221590)
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| Project Period (FY) |
2000 – 2001
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| Keywords | PPARγ / enterocolitis / gene chip / stomach / PSS / schemia / reperfusion / NF-_KB / TNFα |
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| Research Abstract |
Since PPARγ is express endmost abundantly in the colon as well as adipose tissue and has an anti-inflammatory property, we hypothesized that the molecule may have a role in the regulation of gastrointestinal injury. We investigated the hypothesis in 3 systems ; ischemia/reperfusion (I/R) intestinal injury, I/R gastric injury, and DDS colitis. In all systems, PPARγdeficient mice presented with stronger tissue damage than wild type mice, and the tissue damage was markedly prevented by PPARγ ligands. PPARγ ligands, however, failed to show damage-restoring effects in treatment modes. Concerning the mechanism of the tissue protecting effect, PPARγ ligands inhibited activation of NF-_KB, thereby down-regulating inflammatory molecules including cytokines (e.g. TNFα) and adhesion molecules (e.g. ICAM-1). PPARγ is absent from normal stomach, but I/R induced expression in the cytoplasm of the epithelium, and ligands induced nuclear translocation of the molecule. This suggests that PPARγ exerts anti-inflammatory effects by acting as a nuclear transcriptional factor. We also analyzed changes in gene expression induced by PPAEγ signaling comprehensively by a gene chip method. As a result, inflammatory mediator genes, water/electrolyte metabolism-related genes, drug metabolism-related genes, and cancer-related genes were identified. Concerning cytokines, Th1 cytokines including IFNγ were markedly down-regulated by ligand pre-treatment, while Th2 cytokines including IL-4 and IL-10 were up-regulated. This indicated that PPARγ ligands exert anti-inflammatory effects at least in part by changing Th1/Th2 balance.
Pioloitazone given to a patient with ischemic colitis in the acute phase markedly diminished abdominal pain. This suggested that the results obtained in mouse experiments are also true in man.
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Research Products
(8 results)
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[Publications] Nakajima A, Wada K, Miki H, Kubota N, Nakajima N, Terauchi Y, Ohnishi S, Kadowaki T, Blumberg RS, Nagai R, Matsuhashi N: "Endogenous PPARγ mediates anti-inflammatory activity in a model of ischemia-reperfusion injury."Gastroenterlogy. 120. 460-469 (2001)
Description
「研究成果報告書概要(欧文)」より
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[Publications] Osawa E, Nakajima A, Yoshida S, Omura M, Nagase H, Ueno N, Wada K, Matsuhashi N, Ochiai M, Nakagama H, Sekihara H: "Chemoprevention of aberrant crypt foci of the colon by dehydroepiandrosterone"Life Sci. (in press).
Description
「研究成果報告書概要(欧文)」より
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