The molecular mechanisms of initiation, progression, rupture of cerebral aneurysms and development of a preventive treatment for it
| Project/Area Number |
17390399
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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 |
Cerebral neurosurgery
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| Research Institution | Kyoto University |
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Principal Investigator |
HASHIMOTO Nobuo Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (40135570)
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| Co-Investigator(Kenkyū-buntansha) |
NOZAKI Kazuhiko Kyoto University, Graduate School of Medicine, Associate Professor, 医学研究科, 助教授 (90252452)
KITA Toru Kyoto University, Graduate School of Medicine, Professor, 医学研究科, 教授 (60161460)
NAGATA Kazuhiro Kyoto University, Institute for Frontier Medical Sciences, Professor, 再生医科学研究所, 教授 (50127114)
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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 |
¥15,600,000 (Direct Cost: ¥15,600,000)
Fiscal Year 2006: ¥6,000,000 (Direct Cost: ¥6,000,000)
Fiscal Year 2005: ¥9,600,000 (Direct Cost: ¥9,600,000)
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| Keywords | cerebral aneurysm / animal model / IL-1β / apoptosis / linkage analysis / TNF-α / MMP / TIMP |
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| Research Abstract |
We induced experimentally cerebral aneurysms in rats and mice.
Immunohistochemistry and RT-PCR showed the upregulated expression of IL-1β mainly in medial smooth muscle cells. In IL-1β deficient mice, the ratio of advanced aneurysms was significantly reduced and the number of apoptotic cells in aneurysmal walls decreased. These data suggested that IL-1β promoted the progression of cerebral aneurysms by inducing apoptosis in smooth muscle cells.
Immunohistochemistry and RT-PCR showed the expression of MMP-2 and MMP-9 increased in aneurysmal walls with aneurysm progression. In the early stage of aneurysm formation, macrophages accumulated into aneurysmal walls and secreted MMP-2 and-9. The treatment with a selective inhibitor of MMP-2 and-9, Tolylsam, significantly decreased the ratio of advanced aneurysms. These data indicated that MMP-2 and-9 secreted by macrophages promoted the progression of aneurysms.
In RT-PCR, the expression of endogenous inhibitor of MMPs, TIMP-1 and-2, increased in the early stage of aneurysm formation but not in the late stage, making the ratio of MMP/TIMP elevated in advanced aneurysms. In Both TIMP-1 and TIMP-2 deficiency mice, the progression of cerebral aneurysms was promoted, demonstrating the suppressive role of TIMP-1 and-2 in aneurysm progression.
In a linkage analysis of 24 families with cerebral aneurysms, TNF receptor superfamily 13B was proved to be a susceptible gene of human cerebral aneurysm.
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Report
(3 results)
Research Products
(22 results)
