PTH Receptors in Vascular Smooth Muscle Cells

血管平滑肌细胞中的 PTH 受体

• 批准号: 7256381
• 负责人: ALESSANDRO BISELLO
• 金额: $ 26.14万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-07-05 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7256381
• 关键词: 1-Phosphatidylinositol 3-Kinase; Abbreviations; Adaptor Signaling Protein; Affect; Amino Acids; Angioplasty; Arrestin; 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 Hormones; Pathology; Pharmacology; Physiological; Play; Protein Kinase C; Proteins; Proto-Oncogene Proteins c-akt; RAC-Alpha Serine/Threonine Kinase; Regulation; Research Personnel; Research Proposals; Risk; Role; Scaffolding Protein; Signal Transduction; Sirolimus; Smooth Muscle Myocytes; Specificity; System; Therapeutic; Tissues; Transcriptional Activation; Up-Regulation; 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; protein 50 kDa; receptor; response; restenosis; trafficking; tuberoinfundibular peptide 39; vascular smooth muscle cell proliferation

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(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扮演着不同和重要的角色。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症和甲状旁腺功能亢进症，是慢性肾功能衰竭患者死亡的主要原因。PTHrP上调与动脉损伤后内膜增殖有关。尽管如此，对PTH 1R的干预在治疗钙化性血管病变和再狭窄方面具有治疗潜力。甲状旁腺素受体的信号活动具有明显的细胞特异性，事实上，“经典的”甲状旁腺素靶点(成骨细胞和肾脏细胞)的细胞反应与血管平滑肌细胞(VSMC)的细胞反应有根本的不同。此外，VSMC同时表达PTH1R和PTH2R，并暴露于PTH、PTHrP和TIP39。目前对PTH1R和PTH2R在VSMC中作用的具体分子事件知之甚少。我们假设，不同类型的细胞，特别是骨细胞和血管细胞，在信号、调节和运输方面的差异与特定的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)参与了PTH1R的信号特异性和转运。阻滞素是受体脱敏的中心决定因素，并有助于PTH 1R的有丝分裂活性。在这个研究方案中，我们计划：1)研究PTH1R和PTH2 R在VSMC中的配体和细胞特异性信号传递、调节和运输的机制；2)确定PTH1R和PTH2 R在VSMC增殖中抗有丝分裂活性的分子事件；3)确定PTH1R和PTH2 R对原代VSMC增殖和随后的体内动脉损伤的影响。