胆固醇转运子ABCA1调控CD4+T细胞免疫应答抑制动脉粥样硬化的新机制研究

项目名称： 胆固醇转运子ABCA1调控CD4+T细胞免疫应答抑制动脉粥样硬化的新机制研究

项目编号： No.81470564

项目类型： 面上项目

立项/批准年度： 2015

项目学科： 医药、卫生

项目作者： 赵颖

作者单位： 苏州大学

项目金额： 73万元

中文摘要： 动脉粥样硬化的发生发展机制复杂，缺乏理想的治疗药，亟需寻找可调控的靶点。尽管胆固醇转运子ABCA1 具有抗动脉粥样硬化作用，但其作用的靶细胞和机制尚不清楚，这极大地阻碍了其相关治疗靶点的发现。我们前期的研究提示CD4+T细胞可能是骨髓源性ABCA1发挥抗动脉粥样硬化作用的靶细胞。 本研究拟构建T细胞上ABCA1的条件性敲除小鼠, 比较条件敲除鼠与野生型小鼠的CD4+T细胞在发育、表型及功能上的差异, 发现ABCA1调控CD4+T细胞免疫应答的重要功能分子事件, 并在动脉粥样硬化小鼠模型中明确CD4+T细胞上ABCA1的抗动脉粥样硬化作用。最后我们将在人CD4+T细胞上进一步验证ABCA1对CD4+T细胞免疫应答的调控作用，并探讨ABCA1的表达与CD4+T细胞功能和冠心病发病间的相关性。本研究旨在通过对ABCA1抗动脉粥样硬化新机制的探讨，寻找治疗动脉粥样硬化的靶点,为临床提供新的治疗策略

中文关键词： ATP结合盒转运蛋白A1；CD4+；T细胞；动脉粥样硬化

英文摘要： Atherosclerosis is a complex disease with the involvement of many cell types and circulating mediators that result in an inflammatory state. Despite the extensive application of lipid lowering drugs, the high prevalence of myocardial infarction and stoke indicates the urgent need for the development/discovery of new therapeutic strategies/targets. ABCA1, a cholesterol transporter, protects against atherosclerosis. However, the effector cells and mechanisms underlying the atheroprotective effects of ABCA1 are still not clear. This greatly hampers the novel ABCA1-based therapeutic strategy for atherosclerosis. Our previous studies indicate that CD4+ T cells are effector cells for bone marrow-derived ABCA1 in prevention of atherosclerosis. In the current study, we will generate T cell-specific ABCA1 knockout (KO)(ABCA1-CD4/-CD4) mice to determine the regulatory function of ABCA1 on the development, phenotype and function of CD4+ T cells. The important molecular events underlying this regulatory function will be identified, e.g. signaling pathways and the phosphorylation of ABCA1. The atherosclerotic lesion development will be induced in both LDLr-/- and LDLr-/-/ABCA1-CD4/-CD4 mice to determine the anti-atherogenic effects of ABCA1 on CD4+ T cells. Finally, we will test the effect of ABCA1 knockdown on the function of human T cells, and compare the ABCA1 expression and function of CD4+T cells between healthy controls and patients of coronary heart diseases. The current study will unravel novel mechanisms for the atheroprotection of ABCA1: through the regulation of CD4+ T cell-mediated immune responses. Identification of underlying molecular events will likely discover novel promising therapeutic targets for atherosclerosis.

英文关键词： ABCA1 (ATP-binding cassette transport A1);CD4+ T cells;atherosclerosis