Sunday, April 28, 2024
4/28/2024
Project Summary/Abstract The parathyroid hormone (PTH)-related protein (PTHrP) is essential for mammary gland development, placental calcium ion transport, tooth eruption, bone formation and remodeling, and causes hypercalcemia in patients with malignancy. Our current understanding of how endogenous PTHrP (PTHrP1-141) transduces signals through the PTH type 1 receptor (PTHR), a Class B G-protein coupled receptor (GPCR), is largely based on studies done with its N-terminal fragment (PTHrP1-36). However, pilot studies revealed that signaling properties of endogenous PTHrP are distinct from its N-terminal fragment and dependent on heparin/heparan sulfate, a glycosaminoglycan (GAG). The role of extracellular matrix components, such as GAGs, in PTHR signaling and trafficking has largely been ignored. Thus, the goal of this proposal is to determine the molecular and cellular mechanisms by which heparan sulfate controls PTHrP signaling via PTHR. We hypothesize that the interaction between heparin/heparan sulfate and PTHrP maintains local concentrations of the hormone at the cell surface, which enhances the rate of receptor binding and ligand residence time on PTHR, and consequently contributes to location biased signaling mediated by PTHrP. The first Aim will address this hypothesis by characterizing the binding properties of PTHrP and heparin/heparan sulfate interaction using biophysical approaches. The second Aim will employ single-cell and single-molecule optical imaging approaches to determine the functional role of heparin/heparan sulfate and the mechanism by which PTHrP signals via PTHR. The findings of this proposal will provide insight into the ligand biased signaling mechanism of PTHR, and contribute to the overall understanding of GPCR signaling beyond the field of pharmacology.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
