RGS6调控ApoE-/-小鼠动脉粥样硬化的作用及机制研究

动脉粥样硬化(AS)是致残、致死性心脑血管疾病最常见的病因，围绕炎症相关调控因子及机制的研究仍是AS防治领域的重点。G蛋白信号通路调控因子(RGS)6负性调节G蛋白信号功能，可经线粒体和活性氧介导促进炎症反应和凋亡，这些均与AS病理发展密切相关。我们前期研究发现，AS病人外周血巨噬细胞中RGS6的表达降低，且在主动脉内皮细胞中上调RGS6表达可增加细胞内活性氧簇(ROS)和c-Jun氨基末端激酶(JNK)的水平，提示RGS6调控ROS/JNK并参与了AS的发展，但其与AS发生发展的关联及具体机制尚不清楚。因此，我们假设RGS6可通过调控JNK信号通路介导炎症反应参与AS。本研究将采用ApoE−/−小鼠构建RGS6敲除的AS模型，通过检测AS相关的功能、粥样斑块面积及分子生物学、病理表型，阐明RGS6对AS发生发展的影响，探讨其激活JNK等信号通路介导AS的机制，为寻找防治的新靶点提供依据。

Atherosclerosis is the most common cause of ischemic peripheral artery and cardiovascular diseases. Recent studies have focused on strategies to identify the regulatory factors and underlying mechanisms of the inflammatory response in atherosclerosis. Regulator of G protein signaling (RGS) protein 6 can negatively regulate the activity of GPCR subunits, leading to change in its downstream signaling pathways. It can aslo promote inflammation and apoptosis through mitochondria and reactive oxygen species. All these are closely related to the pathogenesis of atherosclerosis. The objective of this proposal is to determine the mechanisms underlying the regulation of RGS6 in atherosclerosis. Our central hypothesis is that RGS6 promotes atherosclerosis through JNK pathway. Firstly, we will generate RGS6 gene knock out in apolipoprotein E-deficient mice and detect the molecular, functional and pathologic change of atherosclerosis (high-fat diet) to determine how RGS6 modulates atherosclerosis. Secondly, we will test the change of the related inflammatory pathways to reveal the potential mechanisms. Understanding the key molecular interactions during atherosclerosis will help us launch new therapeutic targets for the prevention and treatment of atherosclerosis.