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，是全球主要的死亡原因 导致每年约679,000人死亡，相当于每五人中就有一人死于 美国。随着患者被诊断为冠心病的并发症继续增加，这一数字预计还会增加 站起来。目前，他汀类药物是预防冠心病的金标准，它可以降低循环中的血脂含量 同时进行饮食和锻炼的患者。在几十年来死亡率稳步提高之后，总体而言 趋势已开始趋于平缓，目前的药物仅提供了温和的绝对增量益处 动脉粥样硬化斑块破裂，导致心肌梗死、中风和心力衰竭。我们的实验室有 先前证明G蛋白偶联受体PAR2在小鼠和人类中都是增强的 动脉粥样硬化斑块。此外，研究表明，人类抗原R(HUR)的表达增加 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。 虽然我们知道PAR2在动脉粥样硬化的形成中起作用，但PAR2的机制(S) HUR在动脉粥样硬化形成中的作用尚不清楚。了解 PAR2和HUR促进动脉粥样硬化进展的分子机制可能给出新的 洞察潜在的治疗靶点，可以改善冠心病患者的结果并阻止 旧疗法的回报递减。 这项建议的主要目标是研究PAR2和HUR相互作用的机制以及它们的 无论是独立的还是独立的，对动脉粥样硬化发展的贡献。以前使用数据 在我们实验室收集的资料中，我们知道PAR2在动脉粥样硬化中的作用来自于一种非造血细胞 细胞类型，如血管平滑肌细胞(VSMCs)。因此，我们假设PAR2在 VSMCs将HUR重新定位到胞浆，在那里它结合并稳定PAR2 mRNA，上调PAR2 表达和进一步进展的动脉粥样硬化。这一假设将使用两个具体的目标和 由PAR2和HUR基因突变组成的几个小鼠模型，特别是在VSMC中(目标1和目标2 )。我们还将使用各种体外实验来观察HUR结合PAR2 mRNA(AIM 2)作为 以及研究PAR2在VSMC去分化中的作用(目标1)，最近的文献表明 VSMC去分化在动脉粥样硬化进展中的作用。这样做的长期目标是 这项研究旨在进一步阐明PAR2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展。这些结果也可能对该领域产生积极影响，并给出 着眼于潜在的靶点，为冠心病患者开发新的治疗方法。