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FGF21 as a mediator of RPE mitochondrial dysfunction

Award Number: R01EY034002
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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FGF21 as a mediator of RPE mitochondrial dysfunction - 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.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $504,084 )
2026	2026	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	4	4/2/2026	NON-COMPETING CONTINUATION	$504,084
														Subtotal = $504,084

Issue Date FY: 2025 ( Subtotal = $504,084 )
2025	2025	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	3	2/14/2025	NON-COMPETING CONTINUATION	$504,084
														Subtotal = $504,084

Issue Date FY: 2024 ( Subtotal = $527,561 )
2024	2024	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	2	2/23/2024	NON-COMPETING CONTINUATION	$527,561
														Subtotal = $527,561

Issue Date FY: 2023 ( Subtotal = $533,078 )
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	000	1	2/17/2023	NEW	$521,351
2023	2023	THE LELAND STANFORD JUNIOR UNIVERSITY	450 JANE STANFORD WAY	STANFORD	CA	94305	SANTA CLARA	USA	Vision Research	001	1	9/8/2023	NEW	$11,727
														Subtotal = $533,078

Grand Total All Awards = $2,068,807

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FGF21 as a mediator of RPE mitochondrial dysfunction

Award Number: R01EY034002

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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