The role of PAR2 and HuR in programming atherosclerotic vascular smooth muscle cells

PAR2和HuR在动脉粥样硬化血管平滑肌细胞编程中的作用

• 批准号: 10749319
• 负责人: Caris Alyssa Wadding-Lee
• 金额: $ 3.62万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-30 至 2026-09-29
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10749319
• 关键词: Antigens; Arterial Fatty Streak; Arteries; Atherosclerosis; Attenuated; Binding; Blood; Cardiovascular system; Cathepsins; Cause of Death; Cells; Cessation of life; Cholesterol; Complex; Coronary Arteriosclerosis; Cytosol; Data; Development; Diagnosis; Disease; Disease Progression; Environment; Factor Xa; Female; G-Protein-Coupled Receptors; Genetic; Goals; Heart failure; Hematopoietic; Human; Immunoprecipitation; In Vitro; Inflammation; Inflammatory; Injury; Knock-out; Knowledge; Laboratories; Lipids; Literature; Low-Density Lipoproteins; LoxP-flanked allele; Macrophage; Mediating; Mediator; Messenger RNA; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; PAR-2 Receptor; Patients; Peptide Hydrolases; Persons; Pharmaceutical Preparations; Pharmacologic Substance; Phenotype; Process; Proteins; Public Health; Publishing; RNA-Binding Proteins; Role; Site; Smooth Muscle Myocytes; Stains; Stimulation of Cell Proliferation; Stroke; Techniques; Testing; Therapeutic; Trypsin; United States; Up-Regulation; Vacuum; Vascular Smooth Muscle; Vision; Western Blotting; atherosclerotic plaque rupture; attenuation; autosome; cell dedifferentiation; cell type; comorbidity; crosslink; cytokine; diet and exercise; disease diagnosis; exercise regimen; experimental study; feeding; improved; improved outcome; in vivo; insight; mRNA Expression; mRNA Stability; male; mortality; mouse model; mutant; new therapeutic target; novel; novel therapeutics; post-COVID-19; prevent; protein expression; receptor; targeted treatment; trend; vascular contributions

PROJECT SUMMARY/ABSTRACT Coronary artery disease (CAD), the result of atherosclerosis formation, is the leading cause of death globally resulting in approximately 679,000 annual deaths or the equivalent to every one in five deaths occurring in the United States. This number is expected to increase as comorbidities of CAD diagnosed in patients continues to rise. Currently, statins, which lowers the amount of circulating lipids, are the gold standard of preventing CAD in patients with a concomitant diet and exercise regimen. After decades of steadily improving mortality rates, overall trends have begun to plateau and current medications provide only modest absolute incremental benefits from atherosclerotic plaque rupture and resultant myocardial infarction, stoke, and heart failure. Our laboratory has previously demonstrated the G-protein coupled receptor, PAR2, is augmented in both murine and human atherosclerotic plaques. Moreover, studies have demonstrated increased Human Antigen R (HuR) expression at sites of vessel injury, with the potential to bind and stabilize PAR2 mRNA in these inflammatory conditions. Though we know PAR2 contributes to the formation of atherosclerosis, the mechanism(s) in which PAR2 mediates atherosclerosis formation and the role of HuR in atherosclerosis are still unknown. Understanding the molecular mechanisms in which PAR2 and HuR contributes to the progression of atherosclerosis could give new insight into potential targets of therapeutics that could improve the outcomes of CAD patients and put a halt to the diminishing returns of old therapeutics. The primary goal of this proposal is to investigate the mechanisms by which PAR2 and HuR interact and their contributions, both independently and dependently, to atherosclerosis development. Using data previously collected in our lab, we know that the contributions of PAR2 in atherosclerosis derive from a non-hematopoietic cell type, such as vascular smooth muscle cells (VSMCs). Thus, we hypothesize that activation of PAR2 in VSMCs relocates HuR to the cytosol where it binds and stabilizes Par2 mRNA, upregulating PAR2 expression and further progressing atherosclerosis. This hypothesis will be using two specific aims and several mouse models that consist of PAR2 and HuR genetic mutants, specifically in VSMCs (aim 1 and aim 2 respectively). We will also use a variety of in vitro experiments to observe HuR binding PAR2 mRNA (aim 2) as well as investigate the role of PAR2 in VSMC dedifferentiation (aim 1), which recent literature has shown the contributions of VSMC dedifferentiation to the progression of atherosclerosis. The long-term objective of this study is to further elucidate the role of PAR2 in atherosclerosis and, if successful, will advance our knowledge of the development and progression of this disease. These results may also positively impact the field and give sight to potential targets to develop new therapies for CAD patients.

项目摘要/摘要 冠状动脉疾病（CAD）是动脉粥样硬化形成的结果，是全球死亡的主要原因 导致大约679,000人死亡或相当于在 美国。随着患者诊断的CAD合并症的合并症，预计该数字将增加 上升。目前，他汀类药物降低了循环脂质的量，是防止CAD中的黄金标准 饮食和运动方案的患者。经过数十年的稳步提高死亡率，总体总体 趋势已经开始稳定，目前的药物仅提供适度的绝对增量收益 动脉粥样硬化斑块破裂和导致的心肌梗塞，stoke和心力衰竭。我们的实验室有 先前证明的G蛋白偶联受体PAR2在鼠和人类中都得到了增强 动脉粥样硬化斑块。此外，研究表明人类抗原R（HUR）表达增加 在血管损伤部位，有可能在这些炎症条件下结合和稳定PAR2 mRNA。 尽管我们知道PAR2有助于形成动脉粥样硬化，但PAR2的机制 介导的动脉粥样硬化形成，HUR在动脉粥样硬化中的作用仍然未知。了解 PAR2和HUR有助于动脉粥样硬化的进展的分子机制可能会带来新的 深入了解可以改善CAD患者结果并停止的治疗剂的潜在靶标 旧治疗学的回报减少。 该提案的主要目标是调查PAR2和HUR相互作用的机制及其相互作用的机制 对动脉粥样硬化发展的独立和依赖的贡献。以前使用数据 在我们的实验室收集，我们知道PAR2在动脉粥样硬化中的贡献源自非脊髓遍 细胞类型，例如血管平滑肌细胞（VSMC）。因此，我们假设PAR2激活 VSMC将HUR重新定位到结合和稳定PAR2 mRNA的细胞质，上调PAR2 表达并进一步发展动脉粥样硬化。该假设将使用两个具体目标， 几种由PAR2和HUR基因突变体组成的小鼠模型，特别是在VSMC中（AIM 1和AIM 2 分别）。我们还将使用各种体外实验来观察HUR结合PAR2 mRNA（AIM 2） 以及研究PAR2在VSMC去分化（AIM 1）中的作用，最近的文献表明 VSMC去分化对动脉粥样硬化进展的贡献。这个长期目标 研究是为了进一步阐明PAR2在动脉粥样硬化中的作用，如果成功，将提高我们对 这种疾病的发展和发展。这些结果也可能对该领域产生积极影响，并给予 视力到潜在的靶标，以开发CAD患者的新疗法。