Enter the text here that is the new abstract information for your application. This section must be no longer than 30 lines of text. The PTH/PTHrP receptor (PTH1R) plays a pivotal role in regulating mineral ion homeostasis and bone growth. PTH1R binds both parathyroid hormone (PTH) and PTH-related peptide (PTHrP), activating downstream effectors, including Gsα/cAMP/PKA, SIK3 and HDAC4. The biological significance of the PTH1R is underscored by its involvement in several rare human diseases, including Jansen's Metaphyseal Chondrodysplasia (JMC) and Eiken Syndrome (ES). JMC is caused by heterozygous activating PTH1R mutations, e.g. T410R, that result in delayed differentiation of growth plate chondrocytes leading to severe bone deformities and extremely short stature. Patients also exhibit severe hypercalcemia/hypercalciuria, nephrocalcinosis and chronic kidney disease (CKD). ES is caused by homozygous PTH1R mutations that result in delayed chondrocyte differentiation and bone mineralization. Some ES patients show PTH resistance without hypocalcemia. Both the JMC mutation of T410R, which maps to transmembrane helix 6, and the R485X mutation of ES, which truncates the receptor's C-terminal tail, increase the level of basal cAMP signaling by the PTH1R. Basal cAMP signaling by both PTH1R-R485X and PTH1R-T410R can be suppressed in vitro by treatment with a PTH inverse agonist (PTH-IA) ligand, but only that of PTH1R-R485X can be suppressed by overexpressing beta-arrestin 2 (βArr2), suggesting a role for the PTH1R C-tail in modulating the binding of βArr2 and Gsα to the intracellular surface of the PTH1R hepta-helical domain. To define the molecular mechanisms underlying the distinct phenotypes caused by these two PTH1R mutations and thus gain novel insights into fundamental PTH1R biology, we generated "humanized" PTH1R knock-in mice expressing the T410R or R485X disease alleles, and will now characterize the impact of the mutations on bone and growth plate development as well as on bone and kidney physiology. We will further use genetic and pharmacologic tools to determine the roles of ßArr2, SIK3 and HDAC4 in the mutant phenotypes (Aim 1), as well as the potential for novel PTH-IAs, administered by SC injection or minipump infusion, to have therapeutic effects (Aim 2). The overall studies will help advance development of the first treatment options for JMC.