Atherogenic mechanisms of SVEP1, a Novel Human Coronary Artery Disease Locus

人类冠状动脉疾病基因座 SVEP1 的致动脉粥样硬化机制

• 批准号: 10441133
• 负责人: Jared Scott Elenbaas
• 金额: $ 3.35万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-06-01 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10441133
• 关键词: Address; Adhesions; Affect; Affinity; Animal Model; Arterial Fatty Streak; Atherosclerosis; Binding; Biological Assay; Cardiovascular Diseases; Cell Culture Techniques; Cell Differentiation process; Cell Lineage; Cell Proliferation; Cells; Clinical; Clonal Expansion; Complement; Coronary Arteriosclerosis; Data; Development; Differentiation and Growth; Disease; Disease model; Embryo; Exhibits; Exposure to; Extracellular Matrix; Extracellular Matrix Proteins; Foundations; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Genomics; Goals; Histologic; Human; Immobilization; Immunofluorescence Microscopy; Integrin Binding; Integrins; Investigation; Knock-out; Knowledge; Label; Link; Lipids; Measures; Methods; Modeling; Molecular; Mus; Nucleosides; Pathogenesis; Pathway interactions; Phenotype; Physicians; Plasma; Play; Preparation; Process; Production; Protein Region; Proteins; Recombinants; Resources; Risk; Role; SARS-CoV-2 B.1.1.7; Scientist; Serum; Signal Pathway; Signal Transduction; Smooth Muscle Myocytes; Surface Plasmon Resonance; System; Techniques; Testing; Therapeutic; Variant; Vascular Smooth Muscle; atherogenesis; behavior influence; biobank; career; causal variant; cell behavior; cell growth; clinical application; disorder risk; drug development; experimental study; genome-wide; human disease; improved; in vivo; insight; integrin alpha9 beta1; interest; mortality; notch protein; novel; novel strategies; novel therapeutic intervention; novel therapeutics; overexpression; prevent; receptor; risk variant; single-cell RNA sequencing; small molecule; small molecule inhibitor; therapeutic candidate; vascular smooth muscle cell proliferation

PROJECT SUMMARY/ABSTRACT Cardiovascular disease is the leading cause of mortality in the world. It is critical to develop non-lipid therapies to address cardiovascular disease since significant risk remains after successful lipid reduction. By using human disease findings as a starting point for experimental investigation, we can focus our resources on the mechanisms, pathways and therapeutic strategies that are the most applicable to human disease. The Stitziel Lab discovered a variant in the extracellular matrix gene, SVEP1, that positively associates with coronary artery disease. To test if SVEP1 is the causal gene in the risk locus, the lab first generated athero-prone mice that were haploinsufficient for Svep1. These mice were found to exhibit less atherosclerotic plaque burden than controls. Similarly, conditional deletion of Svep1 in mature vascular smooth muscle cells (VSMCs) of mice resulted in dramatically less plaque burden. There is a growing body of evidence that VSMCs play a central role in atherosclerosis, including several disease loci now linked to these cells. In addition to producing SVEP1, VSMCs contain Notch and integrin receptors that we hypothesize bind to SVEP1. I discovered that VSMCs grown on recombinant SVEP1 have increased Notch and integrin signaling, as well as increased transcription of genes involved in cell proliferation and differentiation. SVEP1 induces robust proliferation of primary VSMCs, which is dependent on both Notch and integrin α9β1 signaling. These preliminary findings confirm the contribution of SVEP1 to atherosclerosis, potentially by influencing VSMC proliferation and differentiation in a cell-autonomous manner. Despite these promising leads, the mechanisms by which SVEP1 and its variants contribute to disease have yet to be fully characterized. This project will answer critical, outstanding questions about the molecular and cellular mechanisms by which SVEP1 promotes atherogenesis. I will use complementary molecular techniques, cell culture models and animal models to address these questions. I first aim to determine if SVEP1 binds directly to Notch and integrin receptors and, if so, which regions of the protein contribute to binding affinity. This experiment will also clarify the contribution of each signaling pathway to the overall effects of SVEP1 on VSMCs. The leading risk variant will be included in these studies, since the variant residue is within the putative integrin binding domain of SVEP1. I will then interrogate the cellular mechanisms of SVEP1 in atherogenesis using a murine disease model. This will include performing lineage tracing and single cell RNA sequencing with and without the endogenous production of SVEP1 by neointimal VSMCs. This in vivo approach complements the proposed molecular techniques by focusing on mechanisms in their pathophysiologic context. Successful completion of these aims will reveal the mechanisms by which the common and risk allele of SVEP1 promote atherosclerosis while providing insight into the pathogenesis of the world’s deadliest disease with potential to reveal new therapeutic candidates.

项目总结/文摘