Monday, November 17, 2025 11/17/2025

Adenosine receptor 2A in subretinal fibrosis

Award Number: R01EY033737
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 05/01/2022
PERIOD OF PERFORMANCE END DATE: 08/11/2024

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Adenosine receptor 2A in subretinal fibrosis - PROJECT SUMMARY Subretinal fibrosis, an end-stage fibrous scar of neovascular age-related macular degeneration (nAMD), compromises highly organized anatomical layers and tightly coordinated cellular interactions, inevitably leading to irreversible visual impairment. The current treatment for subretinal fibrosis is limited and therefore, new therapeutic strategies for the inhibition of subretinal fibrosis are imperative. Multiple cell types, including endothelial cells (ECs), retinal pigment epithelium (RPE) cells, macrophages and glial cells, contribute to subretinal fibrosis by either differentiating into mesenchymal-like cells and further differentiating into α-smooth muscle actin-positive myofibroblasts and/or producing profibrotic and proinflammatory factors. However, the underlying mechanisms for these cellular and molecular activities remain poorly defined. Adenosine receptor 2A (Adora2a) has been implicated in various vascular diseases and inflammation. Our preliminary data here show that (i) the level of Adora2a expression was increased in subretinal lesions of laser-induced CNV in mice; (ii) the size of subretinal fibrosis was markedly decreased in lesions of laser–induced CNV in Adora2a-deficient mice; (iii) endothelial-to-mesenchymal transition (EndMT) occurred to choroidal ECs (CECs) and EndMT participated in the formation of subretinal fibrosis in laser-induced mouse CNV; (iv) Tgfb2-induced EndMT was decreased for Adora2a-deficient CECs; (v) macrophage-to-myofibroblast transition (MMT) in laser-induced subretinal fibrotic lesions was markedly reduced in Adora2a-deficient mice; (vi) Adora2a-deficient bone marrow derived macrophages (BMDMs) had a compromised production of profibrotic factors after stimulation with Tgfb2; and (vii) the levels of hypoxia-inducible factor (Hif) 1a or 2a dynamically correlated with those of Adora2a in the above pathological alterations. Thus, we hypothesize that Adora2a- mediated Hif signaling in CECs and infiltrated macrophages enhance fibrotic effects leading to increased formation of fibrotic lesions in CNV. To test our hypothesis, we have generated mice with inducible global Adora2a deficiency in Vldlr-/- mice, endothelial lineage tracing mice, inducible endothelial Adora2a deficiency in C57BL/6j mice, and myeloid Adora2a deficiency in C57BL/6j mice. We established an ex vivo approach to culture mouse CECs and in vitro approaches to generate BMDMs. We will investigate the effect of Adora2a inactivation in CECs and myeloid cells in subretinal fibrosis using specific genetic and pharmacological tools and assess subretinal fibrosis using an integrated approach of in vivo, ex vivo, and in vitro models. Our study will define the role of Adora2a in the development of subretinal fibrosis and provide the basis for using ADORA2A inhibition as a novel approach in the prevention and treatment of blinding retinal disease.


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: 2025 ( Subtotal = $402,276 )
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	001	4	2/17/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$402,276
2025	2025	BAYLOR COLLEGE OF MEDICINE	1 BAYLOR PLZ	HOUSTON	TX	77030	HARRIS	USA	Vision Research	004	4	3/18/2025	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$677,587
2025	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	003	3	3/18/2025	NON-COMPETING CONTINUATION	-$437,751
2025	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	3	2/14/2025	NON-COMPETING CONTINUATION	$0
2025	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	002	2	3/18/2025	NON-COMPETING CONTINUATION	-$239,836
														Subtotal = $402,276

Issue Date FY: 2024 ( Subtotal = $437,751 )
2024	2024	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC	AUGUSTA UNIVERSITY 1120 15TH STREET	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	3	4/9/2024	NON-COMPETING CONTINUATION	$437,751
														Subtotal = $437,751

Issue Date FY: 2023 ( Subtotal = $437,751 )
2023	2023	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	2	3/13/2023	NON-COMPETING CONTINUATION	$437,751
														Subtotal = $437,751

Issue Date FY: 2022 ( Subtotal = $437,751 )
2022	2022	AUGUSTA UNIVERSITY RESEARCH INSTITUTE, INC.	1120 15TH ST STE CJ3301	AUGUSTA	GA	30912	RICHMOND	USA	Vision Research	000	1	4/27/2022	NEW	$437,751
														Subtotal = $437,751

Grand Total All Awards = $1,715,529

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Adenosine receptor 2A in subretinal fibrosis

Award Number: R01EY033737

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 05/01/2022

PERIOD OF PERFORMANCE END DATE: 08/11/2024

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