# FGF21 as a mediator of RPE mitochondrial dysfunction

> **NIH NIH R01** · STANFORD UNIVERSITY · 2023 · $533,078

## Abstract

The retinal pigment epithelium (RPE) nourishes and promotes survival of photoreceptors. The RPE
contains abundant mitochondria, consistent with a metabolically active tissue with a variety of energy intensive
tasks. Our characterization of the retinal phenotype of mice with postnatal RPE-selective ablation of Tfam
(RPEΔTfam) demonstrates the necessity of RPE mitochondrial function for the integrity of this epithelium, and
for the well being of photoreceptors. RPE-selective knockout of Tfam results in RPE-cell autonomous and non-
cell autonomous effects including a progressive loss of photoreceptor function and numbers. Our findings
complement studies implicating the RPE as the site of ocular pathology in individuals with inherited
mitochondrial defects, and support a causal role for for RPE mitochondrial dysfunction in age-related macular
degeneration (AMD). Our preliminary studies have uncovered a signaling pathway that is quiescent in normal
RPE cells and induced by diverse stressors; striking upregulation of FGF21 in the RPE of RPEΔTfam mice and
dispersion to the neural retina implicates this secreted molecule as a critical signal capable of propagating the
negative effects of RPE mitochondrial distress. We propose to test this hypothesis and understand the
mechanisms by which FGF21 affects the stressed mouse retina. In Aim 1, we will use mouse models to
determine the consequences of loss and gain of FGF21 function on retinal phenotype in the context of RPE
mitochondrial dysfunction. In Aim 2, we will determine the FGF21 autocrine and paracrine contributions to the
retinal phenotype in this context, including cellular transcriptional responses. In Aim 3, we will develop
molecular inhibitors of FGF21 and test their efficacy in mouse models of RPE distress. Given the centrality of
RPE mitochondrial function to retinal homeostasis and the relevance of chronic stress responses to human
diseases, including AMD, a mechanistic understanding of the consequences of this RPE-derived mitochondrial
distress signal could have a substantial long term impact from both basic and applied perspectives.

## Key facts

- **NIH application ID:** 10586472
- **Project number:** 1R01EY034002-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Douglas E. Vollrath
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2023
- **Award amount:** $533,078
- **Award type:** 1
- **Project period:** 2023-03-01 → 2028-02-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10586472

## Citation

> US National Institutes of Health, RePORTER application 10586472, FGF21 as a mediator of RPE mitochondrial dysfunction (1R01EY034002-01A1). Retrieved via AI Analytics 2026-05-26 from https://api.ai-analytics.org/grant/nih/10586472. Licensed CC0.

---

*[NIH grants dataset](/datasets/nih-grants) · CC0 1.0*