# Lysophosphatidic acid (LPA) is a novel FGF23 regulator in acute kidney injury.

> **NIH NIH K08** · MASSACHUSETTS GENERAL HOSPITAL · 2021 · $172,800

## Abstract

PROJECT SUMMARY/ABSTRACT
 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 condu...

## Key facts

- **NIH application ID:** 10128449
- **Project number:** 5K08DK124568-02
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** Petra Simic
- **Activity code:** K08 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $172,800
- **Award type:** 5
- **Project period:** 2020-04-01 → 2024-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10128449

## Citation

> US National Institutes of Health, RePORTER application 10128449, Lysophosphatidic acid (LPA) is a novel FGF23 regulator in acute kidney injury. (5K08DK124568-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10128449. Licensed CC0.

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