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.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Research Program Projects (P01)
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Special Emphasis Panel (ZDK1-GRB-9 (O1))
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Malozowski, Saul N
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Massachusetts General Hospital
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Wein, Marc N; Spatz, Jordan; Nishimori, Shigeki et al. (2015) HDAC5 controls MEF2C-driven sclerostin expression in osteocytes. J Bone Miner Res 30:400-11
Manolagas, Stavros C; Kronenberg, Henry M (2014) Reproducibility of results in preclinical studies: a perspective from the bone field. J Bone Miner Res 29:2131-40
Javaheri, Behzad; Stern, Amber Rath; Lara, Nuria et al. (2014) Deletion of a single *-catenin allele in osteocytes abolishes the bone anabolic response to loading. J Bone Miner Res 29:705-15
Portale, Anthony A; Wolf, Myles; Juppner, Harald et al. (2014) Disordered FGF23 and mineral metabolism in children with CKD. Clin J Am Soc Nephrol 9:344-53
Gidon, Alexandre; Al-Bataineh, Mohammad M; Jean-Alphonse, Frederic G et al. (2014) Endosomal GPCR signaling turned off by negative feedback actions of PKA and v-ATPase. Nat Chem Biol 10:707-9
Dasgupta, Debayan; Wee, Mark J; Reyes, Monica et al. (2014) Mutations in SLC34A3/NPT2c are associated with kidney stones and nephrocalcinosis. J Am Soc Nephrol 25:2366-75
Vilardaga, Jean-Pierre; Jean-Alphonse, Frederic G; Gardella, Thomas J (2014) Endosomal generation of cAMP in GPCR signaling. Nat Chem Biol 10:700-6
Nistala, Harikiran; Mäkitie, Outi; Jüppner, Harald (2014) Caffey disease: new perspectives on old questions. Bone 60:246-51
Guo, Jun; Song, Lige; Liu, Minlin et al. (2013) Activation of a non-cAMP/PKA signaling pathway downstream of the PTH/PTHrP receptor is essential for a sustained hypophosphatemic response to PTH infusion in male mice. Endocrinology 154:1680-9
Wesseling-Perry, Katherine; Pereira, Renata C; Tsai, Eileen et al. (2013) FGF23 and mineral metabolism in the early post-renal transplantation period. Pediatr Nephrol 28:2207-15

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