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

• 批准号: 10590681
• 负责人: Nathan Oliver Stitziel
• 金额: $ 54.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10590681
• 关键词: Address; Affect; Affinity; Alleles; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Cardiovascular Diseases; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Characteristics; Coronary Arteriosclerosis; Data; Development; Disease; Extracellular Matrix; Extracellular Matrix Proteins; Functional disorder; Genes; Genetic Polymorphism; Genetic Transcription; Genetic study; Goals; Health; Heterozygote; 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 Deficiency; Protein Region; Proteins; Reagent; Residual state; Risk; Role; Series; Signal Transduction; Site; Smooth Muscle Myocytes; Surface Plasmon Resonance; Testing; Therapeutic; Variant; Vascular Smooth Muscle; 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

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性心血管疾病仍然是心血管疾病的主要原因。 发病率和死亡率。虽然现有的降脂疗法现在可以减少低密度 脂蛋白胆固醇非常低的水平，有一个显着的负担的剩余风险，强调需要 新的非脂质治疗靶点。全基因组关联研究（GWAS）具有很大的潜力， 确定新的治疗靶点，但在很大程度上未能实现这一承诺，部分原因是因果关系， GWAS基因座的基础基因是未知的。通过对蛋白质改变的大规模遗传关联研究， 我们发现了细胞外基质基因SVEP 1的一个变异体， 冠状动脉疾病对血脂无任何影响。我们发现孟德尔 SVEP 1蛋白水平与人类CAD有因果关系的随机化。能够结论性地 为了证明SVEP 1是该风险位点的致病基因，我们建立了SVEP 1的互补小鼠模型。 Svep 1缺陷。我们的初步数据显示SVEP 1是由血管平滑肌细胞（VSMCs）产生的， 动脉壁中动脉粥样硬化斑块和耗竭SVEP 1减少了 动脉粥样硬化基于我们的初步数据，我们假设VSMC衍生的SVEP 1促进了 通过激活整合素和Notch信号传导来影响细胞中VSMC的行为和命运， 自主的方式。在这个提议中，我们提出了以下一系列实验来验证这一假设： 目的1，我们将确定在动脉粥样硬化的发展中SVEP 1的耗竭对细胞的影响;目的2， 我们将明确SVEP 1影响VSMC表型的分子机制;在目标3中，我们将 确定SVEP 1对VSMC的促动脉粥样硬化和细胞效应是否依赖于与其 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来支持所有 提出的研究准备揭示SVEP 1促进动脉粥样硬化的机制， 为CAD的发病机制提供了新的见解，并有可能揭示新的治疗方法。