Fibroblast growth factor-23 (FGF23) is a bone-derived hormone that controls blood phosphate levels by increasing renal phosphate excretion and reducing 1,25-dihydroxyvitamin D3 production. FGF23 levels increase with kidney disease and are a strong independent risk factor for adverse renal outcomes and mortality. However, fundamental understanding of what regulates FGF23 production is lacking. We performed a metabolomic/proteomic screen for renal mediators of FGF23 synthesis and have identified a novel signaling axis whereby kidney derived glycerol-3-phosphate (G-3-P) is converted to lysophosphatidic acid (LPA) in bone, which then stimulates FGF23 synthesis. This proposal focuses on this novel role for LPA, with the central hypothesis that LPA mediated signaling through the LPA receptor 1 (LPAR1) is critical for FGF23 production in acute kidney injury (AKI). Supported by strong preliminary data, we will use Lpar1 knockout mice to dissect this pathway in response to both exogenous LPA administration (Aim 1) and in experimental AKI (Aim 2). Together, these studies seek to establish LPA and LPAR1 as potential therapeutic targets for FGF23 mediated morbidity and mortality in kidney disease, and to serve as a springboard for an independent scientific career at the intersection of nephrology and metabolism. The candidate, Dr. Simic, is dedicated to a career in basic investigation in nephrology. She previously pursued research training in aging and bone biology, but since completing nephrology fellowship in 2018, has shifted her focus to a new area?kidney disease, metabolism, and FGF23 homeostasis. Dr. Simic?s immediate career goals include acquiring the skills described in this grant proposal and publishing first author manuscripts to gain name recognition and to establish herself in academic nephrology. Dr. Simic?s long-term career goal is to become an independent physician-scientist and a leading expert in kidney-bone interactions and mineral metabolism. She will benefit from complementary mentorship from Eugene Rhee (primary mentor; Chief, MGH Adult Nephrology), an expert in kidney metabolism, and Harald Jueppner (co-mentor, Chief, MGH Pediatric Nephrology), a leader in mineral biology. Dr. Simic?s career development plan will capitalize on the training and scientific resources in the MGH Nephrology Division and Endocrine Unit, as well as Harvard Medical School. Drs. Simic, Rhee and Jueppner will meet frequently to discuss both science and career development, and have clearly identified aspects of the research proposed that will form the basis of her independent career. An advisory committee has been formed to evaluate progress, provide additional guidance, and plan future directions. Dr. Simic will present her data regularly both in the MGH Nephrology Division and Endocrine Unit and will be supported to present her work at national meetings. Formal coursework is planned in grant writing, public speaking, responsible conduct of research, bioinformatics, metabolomics, and drug development to further enhance her probability of success as an independent physician/scientist.
FGF23 is a protein made by bones that causes the kidneys to get rid of phosphate. FGF23 levels are increased in acute kidney injury and may raise the risk of death. We will test whether a molecule called LPA causes FGF23 to increase in acute kidney injury, with the goal to make new drugs to treat this condition.
