| Budget Amount *help |
¥3,100,000 (Direct Cost: ¥3,100,000)
Fiscal Year 2006: ¥1,500,000 (Direct Cost: ¥1,500,000)
Fiscal Year 2005: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
A basic HLH-PAS transcription factor, hypoxia inducible factor-1α (HIF-1α) facilitates the adaptation of cells to oxygen deprivation, by regulating the genes that are involved in glucose uptake, angiogenesis, erythropoiesis, and cell survival. When T cells migrate from lymph node or the circulation to peripheral inflammation site for immune response, they should be required to adapt to and function within oxygen tensions much lower than those encountered in circulation system. To investigate the role of HIF-1α in peripheral T cells in vivo, we generated T cell-specific HIF-1α KO mice by crossing HIF-1α floxed mice with proximal lck promoter-driven Cre-transgenic mice. We found that HIF-1α-KO T cells were normally generated in the thymus and their distribution in the spleen, and lymph nodes was unimpaired. In the in. vitro culture conditions, HIF-1α-deficient T cells exhibited undiminished IL-2/IL-2R production and proliferation upon stimulation with either anti-CD3 antibody or Con A. I
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n this fiscal year, we have examined whether T cell-mediated responses in HIF-1α KO mice also show consistent results to in vitro experiment described above.
The inflammatory process mediated by monocytes/macrophages and T cells plays a role in atherosclerosis and vascular remodeling. HIF-1alpha has also been shown to be related to T cell functions; however, its role in inflammation and vascular remodeling still unknown clearly. To use this model would lead to us how HIF-1α in T cells contributes to immune response in vivo.
Cuff placement caused significant neointimal hyperplasia in HIF-1α KO mice compared with the control (intima/media< intima/lumen > ratio: 0.28 <0.31> in HIF-1α KO mice with cuff replacement vs. 0.07 <0.06> in those without cuff replacement). However, there was no obvious exacerbation of cuff-injured vascular remodeling in WT and ARNT KO mice. H＆E staining showed that infiltration of mononuclear cells, including plasma cells, at the adventitia was remarkably increased in HIF-1α KO mice but increased only slightly in WT mice and ARNT KO mice.
The HIF-1 signaling pathway in T cells plays a crucial role in the progression of arteriosclerosis. Understanding the molecular mechanism of how HIF-1 signaling pathway is involved in atherosclerosis will provide a therapeutic target for the development of new drugs against atherosclerosis. Less
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