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Partial epigenetic reprogramming of retinal pigment cells in age-related degeneration, dysfunction, and injury

Award Number: K99EY034938
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 06/30/2025

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Partial epigenetic reprogramming of retinal pigment cells in age-related degeneration, dysfunction, and injury - PROJECT SUMMARY Retinal pigment epithelial (RPE) cell dysfunction and damage are hallmarks of age-related macular degeneration (AMD), the leading cause of blindness in the elderly. While anti-VEGF has revolutionized the management of wet or exudative AMD, there is currently no treatment available for non-exudative AMD. Aging is the major risk factor for RPE degeneration and the development of AMD. During aging, epigenetic changes disrupt youthful DNA methylation patterns, leading to cellular dysfunction and senescence. Partial epigenetic reprogramming via ectopic induction of three Yamanaka factors, Oct4, Sox2, Klf4 (OSK), in retinal ganglion cells was recently reported to reprogram and reverse epigenetic age, leading to vision improvement in aged mice as well as in a mouse glaucoma model. I propose to test the hypothesis that partial epigenetic reprogramming can rescue age-related RPE cell degeneration and function in vivo, prevent RPE cell injury induced by a range of insults in vitro, and inhibit the formation of AMD-like pathologies in a mouse model with the following aims. (i) To determine whether OSK-mediated epigenetic reprogramming can restore RPE morphology and function in aged mice, I will examine the visual function and RPE morphology in aged mice with and without OSK induction by optomotor, ERG, RPE flatmount, and transmission electron microscopy. In addition, I will compare the transcriptomes and epigenomes of RPE from aged mice with and without OSK induction to assess the effect of OSK expression. (ii) To test the ability of OSK-induction in rescuing primary human RPE cells from morphologic and functional changes, as well as cell death following various AMD- associated insults in vitro, including oxidative stress, ox-LDL, and cigarette smoking extract. I will also examine the effect of OSK-induction in iPSC-RPE cells derived from high-risk and low-risk donors with AMD. (iii) Examine the role of OSK induction in NaIO3-treated mice, a short-term injury model that induces regional RPE atrophy, and in RPE specific aged Cfh heterozygous (Cfh+/-) mice fed with a high fat, high cholesterol diet, which have pathological changes mimicking early dry AMD. The results of these investigations will reveal the efficacy and viability of epigenetic reprogramming as a therapeutic strategy for RPE regeneration in vivo. My mentoring panel and the proposed training plan will equip me with new knowledge and skills to study age- related retinal diseases and will catalyze my transition to a career as an independent investigator.


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 = -$2,124 )
2026	2024	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	2	3/24/2026	NON-COMPETING CONTINUATION	-$2,124
														Subtotal = -$2,124

Issue Date FY: 2024 ( Subtotal = $114,039 )
2024	2024	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	2	6/28/2024	NON-COMPETING CONTINUATION	$114,039
														Subtotal = $114,039

Issue Date FY: 2023 ( Subtotal = $114,039 )
2023	2023	SCHEPENS EYE RESEARCH INSTITUTE, INC., THE	20 STANIFORD ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	1	6/9/2023	NEW	$114,039
														Subtotal = $114,039

Grand Total All Awards = $225,954

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Partial epigenetic reprogramming of retinal pigment cells in age-related degeneration, dysfunction, and injury

Award Number: K99EY034938

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 06/30/2025

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