Mechanistic Studies of the Novel Human Coronary Artery Disease Gene SVEP1

项目总结 动脉粥样硬化性心血管疾病，包括冠状动脉疾病(CAD)仍然是 世界范围内的发病率和死亡率。尽管现有的降脂疗法现在可以减少低密度脂蛋白 脂蛋白胆固醇水平很低，有很大的残留风险负担，凸显出需要 新的非脂类治疗靶点。全基因组关联研究(GWAS)具有巨大的潜力 确定新的治疗靶点，但在很大程度上未能兑现这一承诺，部分原因是 Gwas基因座的潜在基因尚不清楚。通过一项大规模的蛋白质改变的遗传关联研究 我们在细胞外基质基因SVEP1中发现了一个变异，它与 冠心病对血脂无任何影响。我们现在已经找到了孟德利安 SVEP1蛋白水平与人类冠心病因果关系的随机化。果断地 证明SVEP1是该风险基因的原因基因，我们建立了互补的小鼠模型 Svep1缺乏。我们的初步数据表明，SVEP1是由血管平滑肌细胞(VSMCs)在 动脉粥样硬化斑块和动脉壁中SVEP1的消耗减少了高血压的发生。 动脉硬化。根据我们的初步数据，我们假设VSMC衍生的SVEP1促进 动脉粥样硬化通过激活整合素和Notch信号来影响细胞内VSMCs的行为和命运- 自主的方式。在这项提议中，我们提出了以下一系列实验来验证这一假设： 目的1，我们将确定耗尽SVEP1在动脉粥样硬化发展中的细胞作用；在目标2， 我们将定义SVEP1影响VSMC表型的分子机制；在目标3中，我们将 确定SVEP1对VSMC的促动脉粥样硬化和细胞效应是否依赖于其与其结合 合作伙伴整合素α9β1。我们的调查团队已经开发出大量的初步数据来支持所有 建议的研究，准备揭示SVEP1促进动脉粥样硬化的机制 为冠心病的发病机制提供新的见解，有可能揭示新的治疗方法。

PROJECT SUMMARY Atherosclerotic cardiovascular disease, including coronary artery disease (CAD) remains a leading cause of morbidity and mortality worldwide. Although existing lipid-lowering therapies can now reduce low-density lipoprotein cholesterol to very low levels, there is a significant burden of residual risk, highlighting a need for novel non-lipid therapeutic targets. Genome-wide association studies (GWAS) hold great potential for identifying novel therapeutic targets but have largely failed to deliver on this promise in part because the causal genes underlying GWAS loci are unknown. Through a large-scale genetic association study of protein-altering variation we discovered a variant in the extracellular matrix gene SVEP1 that positively associated with coronary artery disease without any effect on plasma lipids. We have now found with Mendelian Randomization that SVEP1 protein levels are causally associated with CAD in humans. To conclusively demonstrate that SVEP1 is the causal gene in this risk locus, we generated complementary mouse models of Svep1 deficiency. Our preliminary data show that SVEP1 is made by vascular smooth muscle cells (VSMCs) in the atherosclerotic plaque and that depleting SVEP1 in the arterial wall decreases the development of atherosclerosis. Based on our preliminary data, we hypothesize that VSMC-derived SVEP1 promotes atherosclerosis by activating integrin and Notch signaling to influence the behavior and fate of VSMCs in a cell- autonomous manner. In this proposal, we propose the following series of experiments to test this hypothesis: in Aim 1, we will define the cellular effects of depleting SVEP1 in the development of atherosclerosis; in Aim 2, we will define the molecular mechanisms by which SVEP1 influences VSMC phenotypes; and in Aim 3, we will determine if the pro-atherogenic and cellular effects of SVEP1 on VSMCs are dependent on binding to its partner integrin α9β1. Our investigative team has developed substantial preliminary data to support all proposed studies which are poised to reveal the mechanisms by which SVEP1 promotes atherosclerosis while providing new insights into the pathogenesis of CAD with the potential to reveal novel therapeutic approaches.