HORMONAL CONTROL OF CALCIUM METABOLISM

整体计划说明(由申请人提供) 这个名为“钙代谢的激素控制”的项目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)和甲状旁腺激素相关蛋白(PTHrP)的作用的了解。新的焦点是具有惊人生物学意义的配体/受体构象的异质性，新的细胞系统，以及揭示特定细胞控制的转基因啮齿动物模型。总之，这些方法提供了以前未被认识的甲状旁腺素作用的基本机制，反过来可以导致代谢性骨病和矿物质平衡失调的治疗方法的改变。项目I“PTH和PTHrP与PTH受体的相互作用”(Thomas Gardella，PI)将阐述PTH和PTHrP(以及相关设计的类似物)使用的不同机制，以改变PTH/PTHrP受体的构象，从而改变靶细胞内的信号激活。项目II，“骨中甲状旁腺激素信号的第二信使的遗传分析”(Henry Kronenberg，Pi)，将使用基因改变的小鼠，允许单独分析成骨细胞系细胞上的受体激活腺苷环化酶和磷脂酶C的作用。项目III，“甲状旁腺素作用中的第二信使”(F.Richard Bringhurst，Pi)，将使用基因改变的小鼠和体外研究来解决最近发现的蛋白激酶Cd和转录辅助调节因子CITED1在调节甲状旁腺素对骨骼的作用中的作用。项目IV，“磷酸和钙稳态的肾脏调节”(Harold Juppner和Matthew Mahon，co-Pis)将使用(1)选择性改变体内PTH的矿物离子肾脏反应的转基因小鼠，以确定PTH调节肾脏矿物离子代谢的机制；(2)新开发的体外选择性修饰的肾小管作用细胞模型，该模型研究了转基因小鼠的表型的分子基础，尤其关注细胞结构的特定成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.