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Uncovering Novel Atheroprotective Mechanisms

揭示新的动脉粥样硬化保护机制

基本信息

批准号：
9339541
负责人：
Pampee P Young
金额：
--
依托单位：
VETERANS HEALTH ADMINISTRATION
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-07-01 至 2018-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9339541
关键词：
Address Adhesions Apolipoprotein E Apoptosis Arterial Fatty Streak Atherosclerosis Binding Biomechanics Cardiac Myocytes Cause of Death Cell Survival Cell physiology Cells Clinical Collagen Country Crosslinker Cytoplasmic Protein Data Diagnostic tests Disease Disease Progression Endothelial Cells Endothelium Exhibits Extracellular Matrix Family Focal Adhesion Kinase 1 Functional disorder Generations Genomics Glutamine Goals Human Hyperlipidemia Inflammation Inflammatory Integrins Knockout Mice Laboratories Lead Lesion Lipids Lysine Mediating Methods Mission Modality Modeling Molecular Morbidity - disease rate Mus Muscle Cells Myocardial Infarction Oxidative Stress PIK3CG gene Pathogenesis Phenotype Plant Roots Population Proline Protein Tyrosine Kinase Proteins Role Rupture Signal Transduction Skeletal Muscle Smooth Muscle Myocytes Stratified Epithelium Stress Stroke Structural Protein Testing Therapeutic Thrombus Time Vascular Smooth Muscle Veterans Vietnam apolipoprotein E-3 atheroprotective cancer cell density disability experimental study human disease insight kinase inhibitor macrophage mortality mutant new therapeutic target novel novel strategies overexpression prevent prognostic assays public health relevance selective expression vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): Background: Atherosclerotic lesions underlie the leading cause of death among Veterans and in the developed world. Atheromas consist of vascular smooth muscle cells (VSMCs), inflammatory cells, lipid and extracellular matrix (ECM) underlying a dysfunctional endothelium. Thus far the overwhelming emphasis has been on studying the role of lipids and inflammation in atheroma pathogenesis, leaving important gaps in our understanding of the role of VSMCs. The goal of our laboratory is to gain better understanding of their role and key molecular regulators in order to identify new therapeutic targets to halt disease progression and plaque rupture. Using a genomic screen we identified that the small proline rich repeat protein 3 (SPRR3) is exclusively expressed in atherosclerotic lesions of humans and mice primarily in VSMCs. The SPRR family consists of over a dozen small cytoplasmic proteins first identified in stratified epithelia but more recently found in cardiomyocytes, skeletal and smooth muscle and cancer cells. As yet, their role in cell function is unclear. Objective/hypotheses: To determine SPRR3's role in the pathophysiology of atherosclerosis, we generated the SPRR3-deficient (KO) mouse in the atherogenic apoE-/- background. Preliminary data showed a dramatic increase in lesion size and numbers in SPRR3-/-/apoE-/- mice as compared to apoE-/- mice without increased macrophage density or circulating lipids. Importantly, this model showed advanced lesions with reduced VSMCs in the fibrous cap, intraluminal thrombi and downstream intramural myocardial infarcts, likely due to plaque instability. Primary VSMCs isolated from KO mice demonstrated increased apoptosis but reduced ECM synthesis and PI3K/Akt activation. We also found that SPRR co-immunoprecipitates with FAK. Together, our findings support the central hypothesis that SPRR3 is a unique and significant modulator of atheroma progression and plaque stability, which it does by enhancing Akt-dependent VSMC survival and ECM synthesis within the atheroma microenvironment. Specific aims/methods employed: We will study our hypothesis with the following aims: 1) What is the cellular mechanism by which SPRR3 regulates atheroma progression? In this aim we will investigate whether SPRR3 loss drives disease progression by augmenting VSMC loss within lesions. 2) How does SPRR3 regulate VSMC cellular activity? In this aim, we will determine the cellular effects of SPRR3 and whether SPRR3 regulates these effects by interacting with FAK to modulate PI3K/Akt activation. Relevance to VA mission: Atherosclerosis and its complications underlie the leading cause of death in our largest population of Veterans from the Vietnam and post-Vietnam time period. Our studies have identified a novel atheroprotective factor whose loss results in aggressive disease progression and clinical consequences of plaque rupture. Our studies will result in new insights and therapeutic approaches to this pervasive disease with exceedingly high morbidity and mortality.

描述（由申请人提供）：