Parathyroid hormone (PTH), acting through the PTH receptor (PTHR1), expressed in bone and kidney, plays a vital role in maintaining proper blood levels of calcium and phosphate, and also contributes to the regulation of bone growth and remodeling. PTHrP, acting through the same PTHR1, regulates the development of the skeleton and other tissues. Drugs that target the PTHR1 are of interest because they could potentially be used to treat human diseases, such as osteoporosis and hypoparathyroidism (HPT). Yet PTH(1-34) is the only FDA-approved PTH-based therapy. It is thus used to treat osteoporosis, and, while effective, must be injected once a day. The proposed studies will define the molecular mechanisms by which PTH ligands bind to and activate the PTHR1. They will generate new types of PTH analogs, including signaling selective analogs and novel long-acting ligands that are structurally more stable or have adducts that impair renal clearance, and will assess these analogs for binding to the PTHR1 in vitro, and for actions in animals. Also explored will be new non-peptidic, small-molecule ligands for the PTHR1. Selected ligands will be evaluated in a mouse model of HPT (PTH-null mice) for their capacity to normalize blood calcium. New long-acting PTH analogs will also be tested for their capacities to stimulate bone formation and improve strength when injected into mice at low-frequency intervals, such as once-weekly, and in a dual-therapy mode with the bone-resorption inhibitor, OPG-FC.
The proposed studies will lead to a better understanding of how PTH ligands bind to and activate the PTHR1. They will also provide clues for. how to develop and utilize new PTH ligand analogs for more effective treatment of diseases such as osteoporosis and hypoparathyroidism.
|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|
Showing the most recent 10 out of 166 publications