HORMONAL CONTROL OF CALCIUM METABOLISM

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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.