PTH Receptors in Vascular Smooth Muscle Cells

血管平滑肌细胞中的 PTH 受体

基本信息

批准号：
7599247
负责人：
ALESSANDRO BISELLO
金额：
$ 25.58万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2006
资助国家：
美国
起止时间：
2006-07-05 至 2011-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7599247
关键词：
1-Phosphatidylinositol 3-Kinase Abbreviations Adaptor Signaling Protein Affect Amino Acids Angioplasty Arrestins Arterial Injury Binding Proteins Blood Vessels Cardiovascular system Cells Chronic Kidney Failure Couples Coupling Cyclic AMP-Dependent Protein Kinases Endocytosis Event Functional disorder GTP-Binding Proteins Goals Hyperparathyroidism In Vitro Intervention Lead Ligands Link MAP Kinase Gene Mediating Mitogen-Activated Protein Kinase 3 Mitogen-Activated Protein Kinases Molecular Osteoblasts Osteocytes Parathyroid Hormone Receptor Parathyroid Hormone Receptor 2 Parathyroid Hormone Receptors Parathyroid Hormones Pathology Pharmacology Physiological Play Protein Kinase C Proteins Proto-Oncogene Proteins c-akt Regulation Research Personnel Research Proposals Risk Role Scaffolding Protein Signal Transduction Sirolimus Smooth Muscle Myocytes Specificity System Therapeutic Tissues Up-Regulation Vascular Diseases Vascular System Vascular calcification bone bone cell cell growth regulation cell type desensitization ezrin human PTH protein in vivo kidney cell mortality neointima formation parathyroid hormone-related protein programs receptor receptor-mediated signaling response restenosis trafficking tuberoinfundibular peptide 39 vascular smooth muscle cell proliferation

项目摘要

DESCRIPTION (provided by applicant): The parathyroid hormone (PTH) receptors, PTH1R and PTH2R, and their ligands play diverse and important roles in the pathophysiology and pharmacology of the vascular system. PTH, PTH-related protein (PTHrP), and TIP39 affect vascular tone. Vascular calcification frequently accompanies both hypo- and hyper- parathyroidism and is a major cause of mortality in chronic renal failure. PTHrP up-regulation is associated with intima proliferation after arterial injury. Nonetheless, intervention on the PTH 1R has therapeutic potential for the treatment of calcific vasculopathy and restenosis. The signaling activities of the PTH receptors are remarkably cell-specific, and indeed, the cellular responses of "classical" PTH targets (osteoblasts and kidney cells) are fundamentally different from those of vascular smooth muscle cells (VSMC). Moreover, VSMC express both PTH1R and PTH2R and are exposed to PTH, PTHrP and TIP39. Little is known of the specific molecular events underlying PTH1R and PTH2R actions in VSMC. We hypothesize that the differences of signaling, regulation and trafficking between distinct cell types, specifically bone and vascular cells, are related to the expression and function of particular cytoplasmic adaptor proteins. Recent evidence shows that ezrin-binding protein 50 KDa (EBP50) contributes to signaling specificity and trafficking of the PTH1R. Arrestins are central determinant for receptor desensitization and contribute to the mitogenic activities of the PTH 1R. In this research proposal we plan to: 1) Characterize the mechanisms of ligand- and cell-specific signaling, regulation, and trafficking of the PTH1R and the PTH2R in VSMC; 2) Define the molecular events underlying the anti-mitogenic activity of the PTH1R and PTH2R on VSMC proliferation; 3) Define the effects of PTH1R and PTH2R on proliferation of primary VSMC and following in vivo arterial injury.

描述（由申请人提供）：甲状旁腺激素（PTH）受体、PTH1R和PTH2R及其配体在血管系统的病理生理学和药理学中发挥着多样化且重要的作用。 PTH、PTH 相关蛋白 (PTHrP) 和 TIP39 影响血管张力。血管钙化经常伴随甲状旁腺功能减退和甲状旁腺功能亢进，是慢性肾功能衰竭死亡的主要原因。 PTHrP 上调与动脉损伤后内膜增殖相关。尽管如此，对 PTH 1R 的干预对于治疗钙化性血管病变和再狭窄具有治疗潜力。 PTH 受体的信号传导活动具有明显的细胞特异性，事实上，“经典”PTH 靶标（成骨细胞和肾细胞）的细胞反应与血管平滑肌细胞 (VSMC) 的细胞反应根本不同。此外，VSMC同时表达PTH1R和PTH2R，并暴露于PTH、PTHrP和TIP39。对于 VSMC 中 PTH1R 和 PTH2R 作用的具体分子事件知之甚少。我们假设不同细胞类型（特别是骨细胞和血管细胞）之间信号传导、调节和运输的差异与特定细胞质接头蛋白的表达和功能有关。最近的证据表明，ezrin 结合蛋白 50 KDa (EBP50) 有助于 PTH1R 的信号传导特异性和运输。抑制蛋白是受体脱敏的核心决定因素，并有助于 PTH 1R 的有丝分裂活性。在本研究计划中，我们计划： 1) 表征 VSMC 中 PTH1R 和 PTH2R 的配体和细胞特异性信号传导、调节和运输机制； 2) 定义 PTH1R 和 PTH2R 对 VSMC 增殖的抗有丝分裂活性的分子事件； 3) 定义 PTH1R 和 PTH2R 对原发性 VSMC 增殖和体内动脉损伤后的影响。