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Impact of tissue resident memory T cells on the neuro-immunepathophysiology of anterior eye disease

Award Number: R01EY033712
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 03/08/2023
PERIOD OF PERFORMANCE END DATE: 01/31/2028

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Impact of tissue resident memory T cells on the neuro-immunepathophysiology of anterior eye disease - ABSTRACT T cells are major clinical targets for anti-inflammatory treatment of persistent ocular pain induced by anterior eye diseases such as dry eye, yet identification of which T cell subsets drive the pathophysiology of anterior eye disease remains a topic of intensive preclinical investigation. Emerging data shows that a relatively recently discovered pro-inflammatory subset of T cells that rarely re-enter circulation dominate the T cell niche on the ocular surface of humans but are almost nonexistent in preclinical models of dry eye disease. Establishment of these tissue resident memory T cells (TRM) in the eye requires pathogen exposure or vaccination, and because we house laboratory rodents in unnaturally clean environments, they have extremely limited exposure to pathogens. This lack of immunologic experience has precluded the use of extant rodent models to investigate the impact of TRM in neuro-immune mechanisms of anterior eye disease, and the potential interactions between TRM and nociceptors in ocular inflammation and pain remains a pressing gap in knowledge. We propose to address this gap by infecting mice with a clinically relevant ocular pathogen to establish a population of “human- like” TRM in the eye that can be specifically targeted for activation or depletion. Using this rodent model, we will modulate the activity/presence of TRM and/or nociceptors in the anterior eye to test the central hypothesis that TRM and nociceptors engage in bidirectional neuro-immune interactions that cause ocular pain and inflammation. Additionally, these animals will be used in a desiccating stress model of dry eye disease with and without depletion of resident (TRM), and/or circulating virus-specific CD8+ memory T cells, to determine the relative impact of these experience-dependent memory immune cell populations on dry eye pathophysiology. These studies will gain critical insights into neuro-immune mechanisms that drive the pathophysiology of anterior eye disease and determine how prior viral infection shapes the manifestation of subsequent neuro-inflammation. This work will inform innovative avenues for the treatment of human ocular pain and inflammation and bear broad impact for the field of neuro-immunology through first-ever investigation of TRM interactions with the sensory nervous system.


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 = $514,844 )
2025	2025	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Vision Research	000	4	2/14/2025	NON-COMPETING CONTINUATION	$514,844
														Subtotal = $514,844

Issue Date FY: 2024 ( Subtotal = $443,406 )
2024	2024	DARTMOUTH-HITCHCOCK CLINIC	1 MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Vision Research	000	3	3/4/2024	NON-COMPETING CONTINUATION	$443,406
														Subtotal = $443,406

Issue Date FY: 2023 ( Subtotal = $566,523 )
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Vision Research	000	1	1/23/2023	NEW	$566,522
2023	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Vision Research	002	2	8/24/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$566,522
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Vision Research	001	1	8/24/2023	NEW	$0
2023	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Vision Research	004	2	8/29/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$566,522
2023	2023	DARTMOUTH-HITCHCOCK CLINIC	ONE MEDICAL CENTER DR	LEBANON	NH	03756	GRAFTON	USA	Vision Research	005	2	9/20/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$566,521
2023	2023	TRUSTEES OF DARTMOUTH COLLEGE	7 LEBANON ST	HANOVER	NH	03755	GRAFTON	USA	Vision Research	003	1	8/29/2023	NEW	-$566,522
														Subtotal = $566,523

Grand Total All Awards = $1,524,773

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Impact of tissue resident memory T cells on the neuro-immunepathophysiology of anterior eye disease

Award Number: R01EY033712

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 03/08/2023

PERIOD OF PERFORMANCE END DATE: 01/31/2028

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