Barrestin-mediated desensitization of PTH1R at the intersection of PTH and PTHrP biologic actions

About This Grant

Project Summary/Abstract This proposal describes a 5-year plan for Dr. Portales-Castillo to become an independent investigator with expertise in parathyroid hormone /parathyroid hormone related peptide receptor (PTH1R) signaling in patients with skeletal dysplasias. Dr. Portales completed his clinical nephrology training at the Massachusetts General Hospital (MGH). During his time as a clinical fellow and following his interest in renal osteodystrophy, he learned basic research at the Endocrine Unit in the Laboratories of Drs Jüppner and Gardella, leaders in PTH1R research. Dr. Portales work at MGH included the functional characterization of homozygous PTH1R mutants found in patients with Eiken syndrome. Patients with Eiken syndrome have delayed ossification, i.e gain of function effects on PTHrP pathways at the growth plate, but on the other hand, exhibit resistance to PTH actions in proximal renal tubule (PT). Thus, Eiken syndrome exemplifies a paradox in PTH1R signaling: How can the same receptor lead to gain-of-function effects for the function of one of the ligands (PTHrP) but loss-of-function for the other ligand (PTH)? By performing detailed in vitro analyses, Dr. Portales found that three PTH1R mutants found in patients with Eiken syndrome fail to desensitize when treated with PTHrP but not with PTH. Of special interest for this project, is the PTH1R mutant R485X. The PTH1R-R485X mutation introduces a premature stop codon that truncates the receptor C- , a key molecule for receptor desensitization. Derived from the insights gained from the in vitro findings, a novel humanized mouse model of Eiken syndrome was generated. In his role, as an Assistant Professor at Washington University of St. Louis, Dr. work revealed that delayed ossification in the novel humanized Eiken mice is caused by enhanced response to PTHrP in vivo and that like humans, Eiken mice exhibit resistance to PTH calcemic actions . In separate experiments, Dr. Portales also observed that the mammary fat pad (MFP) of mice with Eiken syndrome is smaller due to enhanced PTHrP actions in adipose tissue. The overall hypothesis of this proposal is that the PTH1R C-tail interactions are required to restrain PTHrP responses at the growth plate and adipose tissue but on the other hand promote PTH response in the PT. To test this hypothesis, the proposal has 3 aims: Aim 1 Aim 2: Aim 3: . Trough the work over the next 5 years with his mentorship team comprising of leaders in bone (Drs. Civitelli, Nickolas, Jüppner and Gardella), adipose tissue (Dr. Brian Finck) and PT (Dr. Humphreys) fields, Dr. Portales can leverage this K08 award to become and independent investigator with expertise in PTH1R signaling.