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Brain-gut-retina axis in diabetic retinopathy

Award Number: R01EY033620
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/01/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Brain-gut-retina axis in diabetic retinopathy - Summary Abstract This application puts for the notion of a brain-gut- retinal axis that becomes dysfunctional in diabetic retinopathy (DR). The innate immune system has been strongly implicated in the pathogenesis of DR, but less is known about the role of the adaptive immune system. At the interface of these two systems is a critical population of cells, Th17 cells, that typically reside in the gut during health. Th17 cells have homeostatic properties, mediating host defense against bacterial and fungal infections; however, it remains unclear how intestinal Th17 cells integrate diverse signals into a set of cellular programs that allow them to maintain tissue homeostasis yet also become pathogenic, serving as primary drivers of tissue inflammation. We have identified a critical role of somatostatinergic neurons in the paraventricular nucleus of the hypothalamus (PVN) in regulation of immune function through “loss of function” studies and “gain of function studies. SST expression is dramatically reduced in the PVN of diabetic animals. Hypothalamic dysfunction, as seen in diabetes, has the capacity to induce injury directly through hyperactivation of sympathetic nerves. Based on preliminary and published data, we put for the hypothesis that: Diabetes-induced loss of inhibitory SST neurons in the PVN drives increased autonomic input to the intestine shifting Th17 cells from a homeostatic to a pathologic state. Pathologic Th17 cells leave the intestine and traffic to areas of tissue injury such as the retina in DR. In the retina the pathologic Th17 cells secrete proinflammatory cytokines that recruitment innate immune cells into the retina exacerbating DR. To examine this hypothesis, we propose the following aims: Aim 1: To test if impaired function of hypothalamic SST neurons in diabetes contributes to hyperactivity of autonomic efferents to the gut and increases activation of enteric neurons. Aim 2: To selectively ablate SST PVN neurons (in the absence of diabetes) and evaluate if this results in increased autonomic input to the gut and a shift from “homeostatic” Th17 cells to a “pathogenic” Th17 cells that migrate to the retina and recruit circulating immune cells. Aim 3: To determine if maintaining hypothalamic SST levels at nondiabetic levels in diabetic mice will preserve the function of homeostatic Th17 cells in the gut and prevent their recruitment to the retina delaying the development of DR. Impact: SST analogues may provide an important complementary strategy for DR management by preventing increased sympathetic drive to the gut and Th17 cell dysfunction.


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 = $524,816 )
2025	2025	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	3	1/16/2025	NON-COMPETING CONTINUATION	$524,816
														Subtotal = $524,816

Issue Date FY: 2024 ( Subtotal = $532,390 )
2024	2024	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	2	1/29/2024	NON-COMPETING CONTINUATION	$532,390
														Subtotal = $532,390

Issue Date FY: 2023 ( Subtotal = $550,644 )
2023	2023	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	1	2/3/2023	NEW	$550,644
														Subtotal = $550,644

Grand Total All Awards = $1,607,850

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Brain-gut-retina axis in diabetic retinopathy

Award Number: R01EY033620

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/01/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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