Ongoing Grants/Projects
GPRC6A Project
GPRC6A identifies a key mechanism that integrates bone, sex steroid, and nutrient factors in the regulation of glycemic control and energy metabolism. GPRC6A appears to be the OcnR (osteocalcin receptor) that mediates the effects of Ocn (osteocalcin) to regulate insulin secretion and production and ß-cell proliferation. GPRC6A likely has broader ligand specificities and tissue functions. GPRC6A may also provide a mechanism to modulate insulin resistance in liver, muscle, and adipose tissues. If so, agonists to GPRC6A may coordinately improve both resistance to insulin in peripheral tissues and ß-cell functions. Such dual actions would distinguish targeting GPRC6A from pharmacological approaches that regulate insulin secretion but have counteractive effects on peripheral tissues that make them problematic as therapeutic agents. GPRC6A also has indirect effects through regulation of other hormones that affect energy metabolism and other metabolic processes. Both direct and indirect actions would generate specific pathways about the ways in which a number of endocrine systems involved in intermediary metabolism may be integrated through this receptor. Growing new knowledge of endocrine networks linking metabolic processes across multiple tissues, such as those involving GPRC6A, will likely improve our understanding of the complex factors contributing to the pathogenesis of a wide variety of endocrine disorders. The integrative physiological activity whereby single receptor activated by multiple, distinct ligands links together the function of multiple organs also provides a new conceptual framework to explain how functional related metabolic pathways related to diet, skeletal health, and reproduction are interconnected.
FGF23 Project
FGF23 is a bone-derived hormone that regulates both systemic phosphate and vitamin D metabolism through a novel bone-kidney axis. FGF23 inhibits renal tubular reabsorption of phosphate through mechanisms independent of PTH as well as reduces circulating 1,25(OH)2D through its dual effects to suppress Cyp27b1 production and to stimulate Cyp24 catabolism of 1,25(OH)2D. FGF23 levels progressively increase during chronic kidney disease (CKD), and FGF23 has been proposed to be the initial adaptive response leading to reductions in 1,25(OH)2D and secondary hyperparathyroidism (HPT) in CKD. Efforts to incorporate the new knowledge regarding the FGF23 bone-kidney axis with the better understood PTH-Vitamin D regulatory network have produced conflicting results and paradoxical findings. Our FGF23 kidney project aims to answer these fundamental questions by using variety of genetic modified mice models.
Other
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Title of Project: Polycystins/TAZ as a novel therapeutic target to treat osteoporosis
(1R61AR073518, NIH/NIAMS, 04/01/2018-03/31/2020)
The goal of this project is to validate the Pkd1/Pkd2/TAZ complex as a therapeutic target in bone, and develop a new class of bone anabolic agents that activate this complex to increased bone mass by stimulating osteoblast-mediated bone formation and inhibit bone marrow adipogenesis. -
Title of Project: Skeletal Functions of Polycystins and TAZ
(1R01AR071930, NIH/NIAMS, 07/01/2018-06/30/2023)
The goal of this project is to investigate the function of Pkd1 and TAZ in bone development and mechanosensing. -
Title of Project: Optimization of Novel Small Molecules to Antagonize FGF-23
(1R01DK121132-01, NIH/NIDDK, 07/01/2019-04/30/2024)
Our goal is pursuing an early-stage preclinical validation of small molecule therapeutic leads that block FGF-23 interactions with the FGFR/α-Klotho complex to treat diseases of FGF-23 excess.