Mechanistic Studies of the Novel Human Coronary Artery Disease Gene SVEP1

人类新型冠状动脉疾病基因SVEP1的机制研究

基本信息

批准号：
10446520
负责人：
Nathan Oliver Stitziel
金额：
$ 56.59万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-04-01 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446520
关键词：
Address Affect Affinity Alleles Arterial Fatty Streak Atherosclerosis Binding Biological Assay Cardiovascular Diseases Cell Lineage Cell Proliferation Cells Characteristics Coronary Arteriosclerosis Data Development Differentiation and Growth Disease Extracellular Matrix Extracellular Matrix Proteins Functional disorder Genes Genetic Polymorphism Genetic Transcription Genetic study Goals Health Human Human Genetics In Vitro Integrins Knockout Mice LDL Cholesterol Lipoproteins Label Lipids LoxP-flanked allele Mediating Mendelian randomization Molecular Morbidity - disease rate Mus Mutate NOTCH3 gene Pathogenesis Pathway interactions Phenotype Plasma Proliferating Protein Region Proteins Reagent Residual state Risk Role Series Signal Transduction Site Smooth Muscle Myocytes Surface Plasmon Resonance Testing Therapeutic Variant Vascular Smooth Muscle base behavior influence cardiovascular disorder risk causal variant cell behavior cell growth experimental study genetic association genome wide association study genome-wide human disease in vivo insight integrin alpha9 beta1 mortality mouse model new therapeutic target notch protein novel novel strategies novel therapeutic intervention receptor risk variant single-cell RNA sequencing stem therapeutic target vascular smooth muscle cell proliferation

项目摘要

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.

项目摘要包括冠状动脉疾病（CAD）在内的动脉粥样硬化心血管疾病仍然是全球发病率和死亡率。尽管现有的降脂疗法现在可以减少低密度脂蛋白胆固醇达到非常低的水平，存在显着的残留风险，强调需要新型的非脂质治疗靶标。全基因组协会研究（GWAS）具有很大的潜力确定新型的热目标，但在很大程度上未能兑现这一诺言，部分原因是 GWAS位置的基因尚不清楚。通过大规模的遗传关联研究变异我们在细胞外基质基因SVEP1中发现了一个变体，该变体与冠状动脉疾病对血浆脂质没有任何影响。我们现在发现了孟德利安 SVEP1蛋白水平有时与人类CAD相关的随机化。结论性证明SVEP1是该风险基因座的因果基因，我们生成了互补的小鼠模型 SVEP1缺陷。我们的初步数据表明，SVEP1是由血管平滑肌细胞（VSMC）制成的动脉粥样硬化斑块和动脉壁中耗尽的SVEP1降低了动脉粥样硬化。根据我们的初步数据，我们假设VSMC衍生的SVEP1促进了动脉粥样硬化通过激活整联蛋白和缺口信号传导来影响细胞中VSMC的行为和命运自主方式。在此提案中，我们提出了以下一系列实验来检验以下假设： AIM 1，我们将定义SVEP1耗尽在动脉粥样硬化发展中的细胞作用；在AIM 2中，我们将定义SVEP1影响VSMC表型的分子机制；在AIM 3中，我们将确定SVEP1对VSMC的促动脉粥样硬化和细胞作用是否取决于与其结合伴侣整合素α9β1。我们的调查团队已经开发了大量的初步数据，以支持所有人提出的研究被毒害以揭示SVEP1促进动脉粥样硬化的机制提供有关CAD发病机理的新见解，并有可能揭示新的治疗方法。