The role of protease-activated receptor 2 in atherosclerosis

蛋白酶激活受体2在动脉粥样硬化中的作用

• 批准号: 10363645
• 负责人: Albert Phillip Owens III
• 金额: $ 40.13万
• 依托单位: UNIVERSITY OF CINCINNATI
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-05-01 至 2024-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10363645
• 关键词: Antigens; Aorta; Arterial Fatty Streak; Arteries; Arthritis; Atherosclerosis; Attenuated; Blood; Blood Vessels; Brain; Cardiovascular Diseases; Cathepsins; Cause of Death; Cell Nucleus; Cells; Chymase; Coagulation Process; Communities; Cytoplasm; Data; Diet; Disease; Disease model; Event; Exposure to; Factor VIIa; Female; GKLF protein; Genetic Polymorphism; Goals; Heart; Heart Hypertrophy; Heart failure; Human; In Vitro; Inflammation; Inflammatory; Intervention Studies; Kruppel-like transcription factors; Laboratories; Lesion; Ligands; Lipid-Laden Macrophage; Lipids; Lipoproteins; Mediating; Mediator of activation protein; Medical; Messenger RNA; Modification; Molecular; Morbidity - disease rate; Mus; Myocardial Infarction; Nutrient; Outcome; Oxides; Oxygen; PAR-2 Receptor; Pathology; Patients; Peptide Hydrolases; Pharmacologic Substance; Pharmacology; Phenotype; Proteins; Public Health; Receptor Signaling; Regulation; Research; Risk; Risk Factors; Role; Rupture; Severities; Signal Transduction; Smooth Muscle Myocytes; Stroke; Systems Analysis; Testing; Therapeutic; Thromboplastin; Thrombosis; Treatment Protocols; Trypsin; Tryptase; Up-Regulation; Vascular Smooth Muscle; atherosclerosis risk; attenuation; cardiovascular disorder risk; cardiovascular effects; diet-induced obesity; genetic analysis; human interactome; improved; macrophage; male; mortality; new therapeutic target; novel; oxidation; receptor; seven-transmembrane G-protein-coupled receptor; thrombotic; transdifferentiation; treatment strategy; uptake

ABSTRACT Arterial thrombosis resulting from plaque disruption is a leading cause of death due to complications arising from myocardial infarction and stroke. Previous studies demonstrate hypercholesterolemic conditions significantly increase the risk of arterial thrombosis via modification of coagulation proteins. These effects occur through oxidation of lipoproteins and subsequent uptake or activation by inflammatory signaling receptors. Tissue factor (TF), the cellular activator of the clotting cascade, is upregulated via oxidized lipoproteins induced by the inflammatory state in atherosclerotic plaques. This allows for accumulation and concentration of TF in atherosclerotic lesions. Importantly, while TF can create a thrombotic event via plaque rupture and exposure to blood; TF can also activate and signal through a cell associated receptor, protease-activated receptor 2 (PAR2). Our strong preliminary data demonstrates deficiency of PAR2 attenuates early (12 weeks) and advanced (24 weeks) atherosclerosis via non hematopoietic cells. Further, we present extensive preliminary studies demonstrating PAR2 signaling results in vascular smooth muscle cell (VSMC) transdifferentiation into a lipid-laden macrophage-like cell via signaling and activation of krüppel-like factor 4 (KLF4) and human antigen R (HuR). Our central hypothesis is that PAR2 regulates VSMC- mediated pathology in atherosclerosis. In Specific Aim 1 we will determine the molecular mechanism of PAR2-mediated VSMC transdifferentiation via activation of KLF4 and HuR. In Specific Aim 2, we will determine the role of VSMC-specific PAR2 deletion and pharmacologic PAR2 inhibition in a relevant disease model of atherosclerosis. Together, our studies will increase our understanding of how PAR2 elicits atherosclerosis and may result in a novel therapeutic target to beneficially effect cardiovascular outcomes.

抽象的 牙菌斑破坏引起的动脉血栓形成是由于并发症的主要死亡原因 由心肌梗塞和中风引起。先前的研究表明高胆固醇血症 通过修饰凝血蛋白，条件大大增加了动脉血栓形成的风险。 这些作用是通过氧化脂蛋白以及随后的摄取或激活而发生的 炎症信号接收器。组织因子（TF）是服装级联的细胞活化剂，是 通过动脉粥样硬化斑块中炎症态引起的氧化脂蛋白上调。 这允许在动脉粥样硬化病变中积累和浓度TF。重要的是，tf 可以通过斑块破裂并暴露于血液来创建血栓性事件； TF也可以激活，并且 通过相关受体，蛋白酶激活的受体2（PAR2）信号。我们的坚强 初步数据表明，PAR2早期减弱（12周）和晚期（24） 几周）通过非造血细胞的动脉粥样硬化。此外，我们提出了广泛的初步 研究表明PAR2信号传导会导致血管平滑肌细胞（VSMC） 通过信号传导和krüppel样的激活转变为富含脂质的巨噬细胞的细胞 因子4（KLF4）和人类抗原R（HUR）。我们的中心假设是PAR2调节VSMC- 动脉粥样硬化中介导的病理。在特定目标1中，我们将确定分子机制 通过激活KLF4和HUR的PAR2介导的VSMC转分解。在特定的目标2中，我们 将确定VSMC特异性PAR2缺失和药物PAR2抑制在A中的作用 动脉粥样硬化的相关疾病模型。一起，我们的研究将增加我们对 PAR2如何引起动脉粥样硬化，并可能导致新的治疗靶点以有益地作用 心血管结局。

项目成果

Advances in Immunotherapy for the Treatment of Adult Glioblastoma: Overcoming Chemical and Physical Barriers.

• DOI: 10.3390/cancers14071627
• 发表时间: 2022-03-23
• 期刊: Cancers
• 影响因子: 5.2
• 作者: Lechpammer M;Rao R;Shah S;Mirheydari M;Bhattacharya D;Koehler A;Toukam DK;Haworth KJ;Pomeranz Krummel D;Sengupta S
• 通讯作者: Sengupta S