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Targeting Fibroblast Growth Factor Signaling as a New Therapeutic Strategy for Meibomian Gland Dysfunction

Award Number: R21EY029106
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2020
PERIOD OF PERFORMANCE END DATE: 01/31/2023

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Targeting Fibroblast Growth Factor Signaling as a New Therapeutic Strategy for Meibomian Gland Dysfunction - PROJECT ABSTRACT Dry eye disease (DED) is a multifactorial disease characterized by desiccation of the ocular surface, potentially leading to permanent injury of the ocular surface and visual impairment. The most common cause of evaporative DED is meibomian gland dysfunction (MGD) which is characterized by glandular atrophy and/or ductal obstruction. Despite the high prevalence of MGD in DED, very little is known about its pathogenic mechanisms, and no targeted and effective treatments exist to restore meibomian gland (MG) function. Current treatments are mostly palliative and unsatisfactory, since they simply aim at symptomatic relief of DED, not at the underlying cause of MGD. A major obstacle in developing new strategies for effective treatment of MGD is the lack of an animal model that recapitulates MGD in humans. A unique mouse model of MGD has been created in which fibroblast growth factor receptor 2 (Fgfr2) is depleted upon induction by doxycycline (Dox). An advantage of this mouse model (referred as Fgfr2CKO ) is that gene deletion can be induced at various stages of the animal’s life and the extent of gene deletion (and thus the extent of MG degeneration and capacity of tissue regeneration) can be modulated by the dosage, or frequency, of doxycycline (Dox) induction treatment. This capability provides a reproducible mouse model of MGD showing strong promise as a model of MGD in humans. In this application, the preliminary studies in the Fgfr2CKO mice support the hypothesis that the FGFR2-signaling pathway plays a critical role not only for MG homeostasis but also in glandular regeneration in adult mice. Therefore, it is plausible that FGF ligand that can act on the FGFR2-signaling pathways can prevent glandular atrophy and promote tissue regeneration, thus serving as MGD-specific therapeutics to treat evaporative DED. The first specific aim of this application is to perform clinical assessment and histopathological analysis of induced MG atrophy and spontaneous regeneration in Fgfr2CKO mice. The outcome will provide the critical benchmarks for Aim 2. The second specific aim is to assess the efficacy of targeting FGFR2 activity by FGF7 as a novel therapeutic strategy for MGD. These preclinical studies in this new mouse model not only will identify potential therapeutic strategies for restoring MG function but also will expand understanding of the pathogenesis of MGD in DED. More importantly, the proposed therapeutic strategy of targeting FGF-signaling pathways has never been explored and may revolutionize the clinical management of MGD.


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: 2024 ( Subtotal = $0 )
2024	2021	UNIVERSITY OF MISSOURI SYSTEM	121 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	000	2	12/12/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $189,756 )
2021	2021	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	000	2	2/18/2021	NON-COMPETING CONTINUATION	$189,756
														Subtotal = $189,756

Issue Date FY: 2020 ( Subtotal = $247,291 )
2020	2020	UNIVERSITY OF MISSOURI SYSTEM	316 UNIVERSITY HALL	COLUMBIA	MO	65211	BOONE	USA	Vision Research	000	1	1/23/2020	NEW	$247,291
														Subtotal = $247,291

Grand Total All Awards = $437,047

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Targeting Fibroblast Growth Factor Signaling as a New Therapeutic Strategy for Meibomian Gland Dysfunction

Award Number: R21EY029106

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2020

PERIOD OF PERFORMANCE END DATE: 01/31/2023

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