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HDAC3/HK2 axis in endothelial metabolic reprogramming and pathological retinal angiogenesis.

Award Number: F31EY039536
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 04/20/2027
PERIOD OF PERFORMANCE END DATE: 04/19/2028

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HDAC3/HK2 axis in endothelial metabolic reprogramming and pathological retinal angiogenesis. - Abstract Retinal pathological angiogenesis (neovascularization) occurs in diabetic retinopathy (DR) and retinopathy of prematurity (ROP). It is characterized by uncontrolled vascular proliferation under hypoxia and the formation of immature and leaky blood vessels. Current treatments have limited efficacy and are associated with adverse effects that warrant exploring new therapeutics. In this proposal, I will detail how I will investigate the novel role of histone deacetylase 3 (HDAC3) in retinal pathological angiogenesis in vitro and in vivo. I have recently shown that HDAC3 mediates retinal endothelial cell (REC) angiogenesis under hypoxia. This angiogenic effect was associated with mitochondrial fission, increased expression of the rate-limiting glycolysis enzyme hexokinase 2 (HK2), and a glycolytic shift. My preliminary data show that HK2 inhibition mitigated REC angiogenesis and decreased basal glycolysis. HK2 is known to be upregulated by hypoxia-inducible factor 1α (HIF-1α) under pathological conditions to increase glycolytic flux. Therefore, I aim to connect HDAC3 and HK2 mechanistically in pathological angiogenesis. I hypothesize that HDAC3 enhances HIF-1α-mediated upregulation of HK2, which metabolically reprograms retinal endothelial cells toward glycolysis, causing mitochondrial dysfunction and leading to increased permeability and pathological angiogenesis. Therefore, both HDAC3 and HK2 are potential therapeutic targets for retinal neovascularization. To investigate this in Aim 1, I will utilize the in vivo model of oxygen-induced retinopathy (OIR) on mouse pups treated with the HDAC3 inhibitor RGFP966 at postnatal days (P) 12 and 14. I will use the same model on endothelial-specific HDAC3 knockout mice by means of a cadherin 5 CRE virus. I will also analyze the impact of HDAC3 on retinal barrier integrity both in vivo and in vitro. These experiments will determine the therapeutic potential of inhibiting HDAC3. In Aim 2, I will subject REC to oxygen-glucose deprivation and reperfusion (OGD/R) model coupled with pharmacological inhibition using the HK2 inhibitor lonidamine, knockdown with siRNA, or plasmid/adenoviral overexpression studies. Endpoints will include cell migration and tube formation assays, co- immunoprecipitation, chromatin immunoprecipitation, western blot, and qPCR. I will also investigate the effects of these modulations on the glycolytic shift and mitochondrial structure and function in endothelial cells. Lastly, I will assess the potential of HK2 inhibition as a treatment in the OIR model. As a trainee, I will learn innovative and clinically relevant techniques to measures retinal thickness and function as well as models of retinopathy commonly used in the field of vision science. Other innovative techniques will include the Seahorse and Oroboros analysis of metabolism, permeability assays, and the use of a CRE adenovirus injected intravitreally into HDAC3 flox mice to induce endothelial HDAC3 knockdown. These experiments will be the first to define the mechanism by which HDAC3/HK2 axis mediates pathological retinal angiogenesis.


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 = $40,778 )
2026	2026	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Vision Research	000	1	8/24/2026	NEW	$40,778
														Subtotal = $40,778

Grand Total All Awards = $40,778

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HDAC3/HK2 axis in endothelial metabolic reprogramming and pathological retinal angiogenesis.

Award Number: F31EY039536

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 04/20/2027

PERIOD OF PERFORMANCE END DATE: 04/19/2028

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