PTH Receptors in Vascular Smooth Muscle Cells

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和药理学中发挥着多样而重要的作用。PTH、PTH相关蛋白（PTHrP）和TIP39影响血管张力。血管钙化常伴随甲状旁腺功能低下和亢进，是慢性肾衰竭死亡的主要原因。PTHrP上调与动脉损伤后内膜增殖有关。尽管如此，干预PTH 1R对治疗钙化性血管病变和再狭窄具有治疗潜力。PTH受体的信号活动具有显著的细胞特异性，事实上，“经典”PTH靶点（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的信号传导、调节和运输的差异与特定细胞质适配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PTH1R的信号特异性和转运。抑制因子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。在本研究计划中，我们计划：1)表征配体和细胞特异性PTH1R和PTH2R在VSMC中的信号传导、调控和运输机制；2)明确PTH1R和PTH2R抑制VSMC增殖的分子机制；3)明确PTH1R和PTH2R对原发VSMC增殖及体内动脉损伤的影响。

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.