Cross-Regulation of Atherosclerosis and Autoimmunity

描述(申请人提供)：心血管疾病，如动脉粥样硬化，是由脂代谢失衡引起的，在美国是主要的死亡原因。流行病学研究表明，系统性自身免疫性疾病患者动脉粥样硬化的发生率较高。相反，已知高脂血症会加速人类和动物模型中的自身免疫性疾病。然而，我们对动脉粥样硬化如何影响自身免疫的发展，反之亦然，还存在着相当大的差距。我们的长期目标是阐明控制动脉粥样硬化和相关自身免疫性疾病发病机制的新的交叉调节机制，这将导致开发新的治疗干预措施来治疗这些毁灭性的疾病。这一R01应用的主要目标是研究动脉粥样硬化和自身免疫T细胞反应之间的关键交叉调节，特别强调Th17反应。我们的中心假设是，导致动脉粥样硬化的条件通过T细胞内在机制促进自身免疫Th17反应，进而加速动脉粥样硬化。其基本原理是，确定交叉调节机制将使我们能够对疾病的发病机制获得多学科的见解。在强大的初步数据的指导下，这一假说将通过两个特定的目标进行验证：1)确定致动脉粥样硬化条件驱动的Th17反应在自身免疫和动脉粥样硬化发展中的作用；2)确定Th17细胞中氧化的低密度脂蛋白信号的细胞内在调节。在第一个目标下，将使用自身免疫性狼疮和动脉粥样硬化的动物模型来检查促动脉粥样硬化条件驱动的Th17细胞在这些疾病的发病机制中的作用。在第二个目标下，将利用生化和遗传工具来剖析氧化低密度脂蛋白信号促进Th17谱系承诺的细胞内在功能的分子机制。我们的方法是创新的，因为它使用了跨学科的概念和独特的强大的遗传工具，通过将高脂血症作为自身免疫介质来检查动脉粥样硬化和自身免疫T细胞反应之间的相互致病调节。这项拟议的研究具有非常重要的意义，因为它有望极大地促进和扩大我们对心血管和免疫系统在动脉粥样硬化和自身免疫发展过程中如何相互作用的理解。最终，这些知识有可能导致开发新的免疫学和药理学策略来治疗动脉粥样硬化和相关的自身免疫性疾病。

DESCRIPTION (provided by applicant): Cardiovascular disease such as atherosclerosis is caused by imbalanced lipid metabolism and represents a leading death cause in United States. Epidemiological studies showed that patients with systemic autoimmune diseases exhibit a higher incidence of atherosclerosis. Conversely, hyperlipidemia has been known to accelerate autoimmune diseases in humans and in animal models. However, there is a considerable gap in our understanding how atherosclerosis impacts the development of the autoimmunity, and vice versa. Our long-term goal is to elucidate novel cross-regulatory mechanisms governing the pathogenesis of atherosclerosis and related autoimmune diseases, which will lead to the development of novel therapeutic interventions for the treatment of these devastating diseases. The primary objective of this R01 application is to investigate the critical cross-regulation between atherosclerosis and autoimmune T cell responses with specific emphasis on Th17 responses. It is our central hypothesis that proatherogenic conditions promote autoimmune Th17 responses through T cell-intrinsic mechanisms which in turn accelerate atherosclerosis. The rationale is that identifying the cross-regulatory mechanisms will enable us to gain multi-disciplinary insights into the pathogenesis of the diseases. Guided by strong preliminary data, this hypothesis will be tested through two specific aims: 1) Determine the role of proatherogenic condition driven Th17 responses in the development of autoimmunity and atherosclerosis; 2) Determine cell-intrinsic regulation of oxidized LDL signaling in Th17 cells. Under the first aim, animal models of autoimmune lupus and atherosclerosis will be used to examine the role of proatherogenic condition-driven Th17 cells in the pathogenesis of these diseases. Under the second aim, biochemical and genetic tools will be used to dissect molecular mechanism for cell intrinsic function of oxidized LDL signaling in promoting Th17 lineage commitment. Our approach is innovative, because it employs interdisciplinary concepts and unique powerful genetic tools to examine mutual pathogenic regulation between atherosclerosis and autoimmune T cell responses by placing hyperlipidemia as an autoimmune mediator. The proposed research is highly significant, because it is anticipated to substantially advance and expand our understanding of how cardiovascular and immune systems cross-talk during the development of atherosclerosis and autoimmunity. Ultimately, such knowledge has the potential to lead to the development of novel immunologic and pharmacologic strategies for the treatment of atherosclerosis and associated autoimmune diseases.