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.

项目总结/摘要 冠状动脉疾病（Coronary artery disease，CAD）是动脉粥样硬化形成的结果，是全球死亡的主要原因 每年约有679，000人死亡，相当于世界上每五个死亡中就有一个死亡。 美国的随着患者中诊断的CAD合并症继续增加， 上升.目前，降低循环脂质量的他汀类药物是预防冠心病的金标准， 同时进行饮食和运动方案的患者。经过几十年的死亡率稳步提高， 趋势开始趋于平稳，目前的药物治疗仅提供适度的绝对增量益处， 动脉粥样硬化斑块破裂并导致心肌梗塞、斯托克和心力衰竭。本实验室 先前证实，G蛋白偶联受体PAR 2在鼠和人中均增强， 动脉粥样硬化斑块此外，研究已经证明增加的人抗原R（HuR）表达 在血管损伤部位，具有在这些炎症条件下结合和稳定PAR 2 mRNA的潜力。 虽然我们知道PAR 2有助于动脉粥样硬化的形成，但PAR 2在动脉粥样硬化形成中的作用机制仍然不清楚。 HuR介导动脉粥样硬化的形成，HuR在动脉粥样硬化中的作用仍不清楚。了解 PAR 2和HuR促进动脉粥样硬化进展的分子机制可能会提供新的 深入了解治疗的潜在靶点，可以改善CAD患者的结局，并阻止 旧疗法的收益递减 本提案的主要目标是研究PAR 2和HuR相互作用的机制及其相互作用机制。 独立和依赖性地促进动脉粥样硬化的发展。使用以前的数据 收集在我们的实验室，我们知道，PAR 2在动脉粥样硬化的贡献来自于非造血 细胞类型，如血管平滑肌细胞（VSMC）。因此，我们假设， VSMC将HuR重新定位到胞质溶胶中，在那里它结合并稳定Par 2 mRNA，上调PAR 2 表达并进一步发展动脉粥样硬化。这一假设将使用两个具体的目标， 由PAR 2和HuR遗传突变体组成的几种小鼠模型，特别是在VSMC中（目的1和目的2 分别）。我们还将使用各种体外实验来观察HuR结合PAR 2 mRNA（目的2）， 以及研究PAR 2在VSMC去分化中的作用（目的1），最近的文献表明， VSMC去分化对动脉粥样硬化进展的作用。长期目标是 这项研究将进一步阐明PAR 2在动脉粥样硬化中的作用，如果成功，将促进我们对 这种疾病的发展和进步。这些结果也可能对该领域产生积极影响， 着眼于潜在的目标，为CAD患者开发新的治疗方法。