# XLas Relative to Gsa in Bone and Mineral Ion Metabolism

> **NIH NIH R01** · MASSACHUSETTS GENERAL HOSPITAL · 2020 · $418,103

## Abstract

Project Summary
Phosphate levels are critical for cellular energy and skeletal development and mineralization.
FGF23 is a key phosphaturic hormone, dysregulated actions/levels of which are the cause of
several inherited bone diseases. FGF23 elevation in response to phosphate retention also
plays a key role in the pathogenesis of and complications related to renal failure. The
mechanisms underlying the production of FGF23 are poorly understood, limiting the ability to
develop effective treatments for these disorders. XLαs is a G protein alpha-subunit, genetic
alterations of which are associated with multiple human diseases. The goal of this proposal is
to investigate the regulatory function of XLαs in FGF23 production and its role in diseases with
dysregulated FGF23 production. Studying XLαs knockout (XLKO) mice as a model to explore
the function of XLαs in humans, we found that XLαs plays a critical role in phosphate
homeostasis during early postnatal development. We also showed that XLαs mediates renal
PTH actions immediately after birth via the PLC/PKC pathway. Our recent work showed that
XLαs ablation results in hyperphosphatemia with significantly reduced serum FGF23. Our
preliminary results strongly indicate that XLαs ablation leads to diminished FGF23 and Fgfr1
mRNA levels, as well as reduced PLC/PKC and ERK1/2 signaling in a bone cell-autonomous
manner. In addition, our preliminary results show that XLαs ablation mitigates the rise of FGF23
induced by acute kidney injury in mice. Therefore, we hypothesize that XLαs plays a critical role
in the production of FGF23 in bone. In Aim 1, we will determine (a) the role of XLαs/PLC/PKC
signaling in FGF23 production, and (b) the mechanism by which XLαs regulates ERK1/2
activation. In Aim 2, we will test the hypothesis that XLαs contributes to PTH-induced FGF23
production via the PLC/PKC and/or ERK1/2 pathway. We will also address the hypothesis that
the interaction of XLαs with SNX9, dynamin, RACK1 and/or IQGAP1 is critical for XLαs-
mediated FGF23 production. In Aim 3, we will determine whether XLαs ablation mitigates the
elevated serum FGF23 levels in a mouse model of (a) acute kidney injury and (b) chronic kidney
disease. Results of the proposed experiments will provide novel mechanistic insights into the
regulation of FGF23 production and will also identify potential drug targets for treating patients
with dysregulated FGF23 levels. Moreover, our studies will provide mechanistic insights into the
cellular actions of XLαs in bone and enhance the knowledge of its roles in human diseases.

## Key facts

- **NIH application ID:** 9830043
- **Project number:** 5R01DK073911-12
- **Recipient organization:** MASSACHUSETTS GENERAL HOSPITAL
- **Principal Investigator:** MURAT BASTEPE
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $418,103
- **Award type:** 5
- **Project period:** 2007-08-01 → 2021-11-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9830043

## Citation

> US National Institutes of Health, RePORTER application 9830043, XLas Relative to Gsa in Bone and Mineral Ion Metabolism (5R01DK073911-12). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/9830043. Licensed CC0.

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