Molecular genetic analyses of the role and regulation of the regenerative and repairing molecules in deeling lung fibrosis
| Project/Area Number |
14370199
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| Research Category |
Grant-in-Aid for Scientific Research (B)
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| Allocation Type | Single-year Grants |
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| Section | 一般 |
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| Research Field |
Respiratory organ internal medicine
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| Research Institution | Tokyo Medical University (2004)
Juntendo University (2002-2003) |
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Principal Investigator |
SETOGUCHI Y. Tokyo Medical University, Medicine, Associate Professor, 医学部, 助教授 (90206649)
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| Co-Investigator(Kenkyū-buntansha) |
鈴木 孝次 順天堂大学, 医学部, 助手 (90338369)
中尾 篤人 順天堂大学, 医学部, 講師 (80317445)
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| Project Period (FY) |
2002 – 2004
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| Project Status |
Completed (Fiscal Year 2004)
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| Budget Amount *help |
¥9,200,000 (Direct Cost: ¥9,200,000)
Fiscal Year 2004: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2003: ¥2,800,000 (Direct Cost: ¥2,800,000)
Fiscal Year 2002: ¥3,600,000 (Direct Cost: ¥3,600,000)
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| Keywords | TGF-β / Smad / fibrosis / regeneration / repairing / adenovirus vector / fibroblast / myofibroblast / 肺 / 線維化 / 遺伝子 / myofibroblast / Smad7 / Smad2 / Smad3 / colla / γ-インターフェロン / 再生修復 / MAP |
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| Research Abstract |
Myofibroblast has been demonstrated in areas of active fibrosis in patients with IPF and appears to originate from fibroblast under the influence of various factors. Especially, TGF-b1 is well known to induce the phenotypic modulation of fibroblasts to myofibroblasts. Smad are a family of signal transducer proteins with Smad3 mediating directly signaling from activated TGF-b1 receptor type I. Samd7 is intracellular antagonist for TGF-b signaling. Based upon these knowledges, we evaluated the phenotypic modulation of human lung fibroblast to myofibroblast characterized by a-smooth muscle actin (aSMA) in two parameters that are the contractility as mechanical property and aSMA expression, by using two type of adenovirus encoding Smad3 and Smad7 respectively. Overexpression of Smad3 alone significantly enhanced collagen gel contraction by fibroblasts when compared with fibroblast overexpressing a control LacZ. Addition of a very low concentration of TGF-b1 that did not affect the collagen gel contraction by itself enhanced contraction by fibroblast over-expressing Smad3. Smad3-over-expressed HLF expressed aSMA expression in the absence of TGF-b1. In contrast, over-expression of Smad7 in HLF resulted in suppression of TGF-b1-mediated collagen gel contraction and aSMA expression Furthermore, Fibroblast or myofibroblast like cells isolated from patients with IPF I(IPF cells) revealed more enhanced gel contraction than normal HLF in the presence of TGF-b1 and aSMA expression in the absence of TGF-b1. Over-expression of Smad7 attenuated gel contraction and aSMA expression in IPF cells. Our data suggest that over-expression of Smad7 may be feasible therapy for IPF and over-expression of Smad3 alone could elicit phenotypic modulation of fibroblast to myofibroblast.
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Report
(4 results)
Research Products
(31 results)
