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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，PTH 1 R和PTH 2 R，及其配体在血管系统的病理生理学和药理学中发挥着多种重要作用。PTH、PTH相关蛋白（PTHrP）和TIP 39影响血管张力。血管钙化常伴随甲状旁腺功能减退和亢进，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生相关尽管如此，对PTH 1 R的干预具有治疗钙化性血管病变和再狭窄的治疗潜力。PTH受体的信号传导活性是显著的细胞特异性的，并且事实上，“经典”PTH靶（成骨细胞和肾细胞）的细胞应答与血管平滑肌细胞（VSMC）的细胞应答根本不同。此外，VSMC表达PTH 1 R和PTH 2 R，并暴露于PTH、PTHrP和TIP 39。很少有人知道的特定的分子事件PTH 1 R和PTH 2 R的行动在VSMC。我们假设不同细胞类型，特别是骨和血管细胞之间的信号传导，调节和运输的差异，与特定的细胞质衔接蛋白的表达和功能有关。最近的证据表明，ezrin-binding protein 50 KDa（EBP 50）有助于PTH 1 R的信号特异性和运输。抑制蛋白是受体脱敏的中心决定因素，并有助于PTH 1 R的促有丝分裂活性。在这项研究计划中，我们计划：1）表征配体和细胞特异性信号，调节和运输的PTH 1 R和PTH 2 R在VSMC的机制; 2）定义的分子事件的PTH 1 R和PTH 2 R对VSMC增殖的抗促有丝分裂活性的基础; 3）定义PTH 1 R和PTH 2 R对原发性VSMC的增殖和以下在体内动脉损伤的影响。