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Role of Arginase 1 in Retinal Ischemia-Reperfusion Injury

Award Number: R00EY029373
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2019
PERIOD OF PERFORMANCE END DATE: 01/31/2025

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Role of Arginase 1 in Retinal Ischemia-Reperfusion Injury - PROJECT SUMMARY Retinal ischemia is a major cause of vision loss in common retinal disease conditions including diabetic retinopathy, glaucoma, retinopathy of prematurity, and vein occlusion. This project aims to define the mechanisms of retinal ischemic injury and identify new therapeutic targets. My long-term career goal is to pursue a distinguished career in vision research and academia. I will achieve this through establishing a strong independent research program in an academic institution that promotes interdisciplinary biomedical science and translational research. My short-term goal is to attain intensive training and supervised career development skills that are required for my career transition to become an independent investigator. Securing this award will provide me with the necessary training to achieve my short- term goals and will be the first step towards independence and achieving my long-term goals. My mentor's lab has demonstrated the involvement of the arginase enzyme in retinal neurovascular diseases. Arginase has two isoforms. Building upon the lab's finding that the mitochondrial isoform, arginase 2 (A2), has a deleterious role in retinal ischemia-reperfusion (IR) injury, I developed a project focusing on the neurovascular protective role of the cytosolic isoform arginase 1 (A1). My recently published paper shows a neuroprotective role of A1 expression in myeloid cells. Arginase competes with nitric oxide synthase (NOS) for their common substrate L-arginine. Nitric oxide (NO) produced by inducible NOS (iNOS) causes neurovascular degeneration. I predict that A1 upregulation in myeloid cells limits iNOS-derived nitrative and oxidative stress and reduces inflammation through its downstream metabolites ornithine and putrescine. Putrescine is the precursor of polyamines and it is formed from ornithine by ornithine decarboxylase (ODC, the rate-limiting enzyme in polyamine biosynthesis). These metabolites have been shown to promote reparative myeloid cells through chromatin modification. In line with this, my preliminary data show that histone deacetylase (HDAC) 3 is increased in the absence of A1 in both IR-injured retinas and stimulated macrophages. HDAC3 is essential for macrophage inflammatory gene transcription and it has been shown to suppress A1 expression. Herein, I propose a novel suppressive effect of A1 on HDAC3. My central hypothesis predicts that myeloid A1 protects against retinal IR injury through ODC-mediated suppression of HDAC3. I will be using mice with myeloid-specific deletion of A1, ODC and HDAC3, as well as the investigational drug, BCT-100 (a PEGylated form of arginase 1), together with primary macrophages isolation and treatment with inhibitors for HDAC3 or arginase downstream enzyme, ODC. My goal is to achieve the following objectives: A) Determine the effect of manipulating the arginase pathway on myeloid cells infiltration / activation in retinal IR injury and the therapeutic potential of BCT- 100. B) Describe the cross talk between the arginase pathway and HDAC3 and determine whether A1 in myeloid cells mediates its protective effect through suppression of HDAC3.


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 = $312,565 )
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Vision Research	001	5	2/7/2024	SUPPLEMENT FOR EXPANSION	$63,565
2024	2024	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Vision Research	000	5	2/5/2024	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $312,565

Issue Date FY: 2023 ( Subtotal = $292,657 )
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Vision Research	001	4	9/13/2023	SUPPLEMENT FOR EXPANSION	$43,657
2023	2023	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Vision Research	000	4	2/21/2023	NON-COMPETING CONTINUATION	$249,000
														Subtotal = $292,657

Issue Date FY: 2022 ( Subtotal = $260,502 )
2022	2022	UNIVERSITY OF ARKANSAS SYSTEM	4301 W MARKHAM ST SLOT 812 BIO-MED BLDG 1 STE 102	LITTLE ROCK	AR	72205	PULASKI	USA	Vision Research	000	3	1/20/2022	EXTENSION WITH OR WITHOUT FUNDS	$249,000
2022	2022	UNIVERSITY OF ARKANSAS FOR MEDICAL SCIENCES	4301 W MARKHAM ST	LITTLE ROCK	AR	72205	PULASKI	USA	Vision Research	001	3	2/15/2022	EXTENSION WITH OR WITHOUT FUNDS	$11,502
														Subtotal = $260,502

Grand Total All Awards = $865,724

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Role of Arginase 1 in Retinal Ischemia-Reperfusion Injury

Award Number: R00EY029373

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2019

PERIOD OF PERFORMANCE END DATE: 01/31/2025

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