| Project/Area Number |
13670453
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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 |
内科学一般
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| Research Institution | TOYAMA MEDICAL AND PHARMACEUTICAL UNIVERSITY |
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Principal Investigator |
KISHI Hiroyuki Toyama Medical and Pharmaceutical University Faculty of Medeicine Associate Professor, 医学部, 助教授 (60186210)
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| Project Period (FY) |
2001 – 2002
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| Project Status |
Completed (Fiscal Year 2002)
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| Budget Amount *help |
¥3,600,000 (Direct Cost: ¥3,600,000)
Fiscal Year 2002: ¥1,300,000 (Direct Cost: ¥1,300,000)
Fiscal Year 2001: ¥2,300,000 (Direct Cost: ¥2,300,000)
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| Keywords | apoptosis / T-lymphocyte / T cell receptor / MAP kinase / Bax / mitochondria / microsome / caspase activated DNase / T細胞抗原受容体 / 胸腺細胞 / p38MAPキナーゼ |
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| Research Abstract |
It is supposed that the auto-reactive T cells are involved in the development of autoimmune diseases. Auto-reactive T cells are usually eliminated from the host by apoptosis that is induced through TCR-signals in the thymus or in the periphery. Dysfunction of the immune surveillance system leads to appearance of auto-reactive T cells in the periphery. In this study, we investigated the TCR signals that induce apoptosis in thymocytes or T cells to unravel the mechanism of the development of autoimmune diseases. First, we analyzed the role of mitochondria in TCR-induced apoptosis of thymocytes and showed that activated p38 kinase pathway by TCR-stimulation induces translocation of Bax to mitochondria, causing DYm-disruption, and the release of cytochrome c, which finally induces caspase-3-mediated apoptosis in thymocytes. Second, we investigated the localization and the function of caspase-activated deoxyribonuclease (CAD) and its inhibitor (ICAD), which play a central role in chromatin fragmentation in apoptotic cells, in thymocytes prior or post in vivo TCR-stimulation. We showed that TCR-engagement of thymocytes induced caspase-3-dependent activation of CAD localized not only in cytosol but also in microsome, leading to their translocation to nuclei and the resulting DNA fragmentation in harmony. These results will prompt us to analyze the TCR-induced apoptosis signals in T cells from patients of autoimmune diseases.
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