HORMONAL CONTROL OF CALCIUM METABOLISM

总体说明（由申请人提供） 本计划项目“钙代谢的激素控制”汇集了来自多个学科的研究人员，以促进对甲状旁腺激素（PTH）和甲状旁腺相关蛋白（PTHrP）作用的理解。有一个新的焦点配体/受体构象的异质性与令人惊讶的生物学意义，新的细胞系统，并强调转基因啮齿动物模型，揭示特定的细胞控制。总之，这些方法提供了对以前未被认识的PTH作用的基本机制的深入了解，这反过来又可以导致代谢性骨病和矿物质稳态紊乱的治疗的变化。项目I，“PTH和PTHrP与PTH受体的相互作用”（托马斯Gardella，PI），将解决PTH和PTHrP（和相关设计的类似物）使用的不同机制，以改变靶细胞内信号激活的方式改变PTH/PTHrP受体的构象。项目II，“骨中PTH信号传导中第二信使的遗传分析”（亨利Kronenberg，PI），将使用遗传改变的小鼠，允许单独分析成骨细胞谱系细胞上受体激活腺苷酸环化酶与磷脂酶C的作用。计划三：“第二次PTH行动信息”（F。理查德Bringhurst，PI），将使用基因改变的小鼠和体外研究，以解决最近确定的蛋白激酶C d和转录辅助调节CITED 1在介导PTH对骨的作用。项目IV，“磷酸盐和钙稳态的肾脏调节”（Harold Luppner和Matthew Mahon，co-Pis）将使用（1）在体内选择性改变PTH的矿物质离子肾反应的遗传改变小鼠，以确定PTH调节肾矿物质离子代谢的机制;和（2）新开发的体外肾小管作用的选择性修饰的细胞模型，其检查遗传改变的小鼠的表型的分子基础，特别关注细胞结构的特定组分在磷酸盐稳态中的作用。

DESCRIPTION OF OVERALL PROGRAM (provided by applicant) This Program Project, "Hormonal Control of Calcium Metabolism," brings together investigators from multiple disciplines to advance understanding of the actions of parathyroid hormone (PTH) and parathyroid hormone-related protein (PTHrP). There is a new focus on heterogeneity of ligand/receptor conformations with surprising biological implications, novel cellular systems, and emphasis on genetically modified rodent models that reveal specific cellular controls. Together, these approaches provide insight into previously unappreciated basic mechanisms of PTH action that in turn can lead to changes in therapy of metabolic bone disease and disorders of mineral homeostasis. Project I, "PTH and PTHrP Interaction with PTH Receptors" (Thomas Gardella, PI), will address the divergent mechanisms used by PTH and PTHrP (and related designed analogs) to change the conformation of the PTH/PTHrP receptor in ways that alter signal activation within target cells. Project II, "Genetic Analysis of Second Messengers in PTH Signaling in Bone" (Henry Kronenberg, PI), will use genetically altered mice that permit separate analyses of the roles of activation of adenylate cyclase versus phospholipase C activation by receptors on cells of the osteoblast lineage. Project III, "Second Messengers in PTH Action" (F. Richard Bringhurst, PI), will use genetically altered mice and in vitro studies to address recently identified roles of protein kinase C d and the transcriptiorial co-regulator CITED1 in mediating the actions of PTH on bone. Project IV, "Renal Regulation of Phosphate and Calcium Homeostasis" (Harold Juppner and Matthew Mahon, co-Pis) will use (1) genetically altered mice with selective alteration of mineral ion renal responses of PTH in vivo to determine the mechanisms by which PTH regulates renal mineral ion metabolism; and (2) newly developed selectively modified cell models of renal tubular action in vitro that examine the molecular basis of the phenotypes of the genetically altered mice, with a particular focus on the role of specific components of cellular cytoarchitecture in phosphate homeostasis.