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PKA and Epac1 inhibit TLR4 to protect the diabetic retina

Award Number: R01EY030284
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 01/01/2020
PERIOD OF PERFORMANCE END DATE: 12/31/2025

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PKA and Epac1 inhibit TLR4 to protect the diabetic retina - Diabetic retinopathy is the leading cause of blindness in working age adults; however, much of this blindness occurs in the later phases of the disease due to proliferative disease or macular edema. Recently, the role of inflammation has become a focus of potential therapies targeted to treat earlier stages and/or prevent progression of the disease. While it is clear that a large number of cytokines/chemokines are increased in the diabetic retina, the role of innate immunity has only recently been investigated. Recent work has demonstrated that toll-like receptors (TLRs) are altered in diabetes. Work has also shown that TLR4 is increased in the streptozotocin-induced diabetic retina. Additionally, TLR4 may have actions in retinal endothelial cells (REC), as both TLR2/4 pathways are active in these retinal cells. Our preliminary data has expanded on those findings to demonstrate that β-adrenergic receptors can decrease TLR4 signaling in the diabetic mouse retina, as well as in both REC and retinal Müller cells. Supporting our findings in retina, studies in macrophages also demonstrate that β-adrenergic receptors can regulate TLR4. The response to Compound 49b was blocked when Epac1 or PKA were knocked down by siRNA, suggesting these proteins act as damage associated molecular pattern molecules (DAMPs) regulating TLR4 signaling in the diabetic retina. Our primary hypothesis for this proposal is that PKA and Epac1 can regulate TLR4 and may represent a key pathway that controls retina damage in diabetes. Our overall goal is to better understand the role of downstream mediators of β-adrenergic receptors in the regulation of TLR4 signaling in the diabetic retina, with the intent of identifying key pathways in innate immunity that can be targeted for novel therapeutics. !


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 = $351,262 )
2024	2024	WAYNE STATE UNIVERSITY	5700 CASS AVE STE 4900	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	5	12/7/2023	NON-COMPETING CONTINUATION	$351,262
														Subtotal = $351,262

Issue Date FY: 2023 ( Subtotal = $351,262 )
2023	2023	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	4	1/11/2023	NON-COMPETING CONTINUATION	$351,262
														Subtotal = $351,262

Issue Date FY: 2022 ( Subtotal = $340,723 )
2022	2022	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	3	1/24/2022	NON-COMPETING CONTINUATION	$340,723
														Subtotal = $340,723

Issue Date FY: 2021 ( Subtotal = $340,723 )
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Vision Research	001	2	2/22/2021	NON-COMPETING CONTINUATION	$24,588
2021	2021	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	2	12/18/2020	NON-COMPETING CONTINUATION	$316,135
														Subtotal = $340,723

Issue Date FY: 2020 ( Subtotal = $351,262 )
2020	2020	WAYNE STATE UNIVERSITY	5057 WOODWARD STE 13001	DETROIT	MI	48202	WAYNE	USA	Vision Research	000	1	12/17/2019	NEW	$351,262
														Subtotal = $351,262

Grand Total All Awards = $1,735,232

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PKA and Epac1 inhibit TLR4 to protect the diabetic retina

Award Number: R01EY030284

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 01/01/2020

PERIOD OF PERFORMANCE END DATE: 12/31/2025

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