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Lacritin Regulation of Homeostasis and Ocular Surface Health

Award Number: R01EY032956
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2021
PERIOD OF PERFORMANCE END DATE: 07/31/2026

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Lacritin Regulation of Homeostasis and Ocular Surface Health - Dry eye is a chronic disruption of ocular surface homeostasis. Evidence is accumulating for tear protein 'lacritin' and its natural C-terminal proteoforms 'N-94' and 'N-94/C-6' as master regulators of ocular surface homeostasis. Accordingly, their selective deficiency or absence in dry eye may be viewed as a major risk factor or even cause of dry eye for which replacement therapy may be a logical treatment approach. Indeed, in NCT03226444, a recent large multi-center, randomized, placebo-controlled, double masked phase 2 clinical trial, topical N-94/C- 6 significantly restored homeostasis within two weeks in Primary Sjögren's Syndrome dry eye - the most severe dry eye group. Although we understand in general how lacritin works, many details are missing - most notably the identity of the signaling receptor, and gaps in proximal and distal signaling. We recently performed unbiased, genome-wide CRISPR/Cas9 death screens. Our death screens identified genes that when disrupted by sgRNA/Cas9 editing abrogated the capacity of N-94 to restore homeostasis of cultured human corneal (HCE-T) cells stressed with lethal doses of IFNγ and TNF in an in vitro model of dry eye. Out of 19,114 genes targeted by 76,441 sgRNA's, with 1,000 controls, GPR87 was the top receptor hit as validated by targeted CRISPR/Cas 9 editing, shRNA knockdown without or with GPR87 cDNA complementation, and syndecan-1 pulldown. GPR87 is expressed in the cornea, shares lacritin signaling mediators (pertussis toxin sensitive G-protein, IP3, calcium, NFAT), and although considered by some to be deorphanized as a lysophosphatidic acid (LPA) receptor, a recent well-controlled study by others failed to detect specific LPA binding in competition nor functional experiments. Nor does LPA rescue HCE-T cells. Our working hypothesis is that GPR87 with syndecan-1 are essential elements of the lacrimal - ocular surface axis. Our immediate goal is to elucidate how GPR87 interacts with syndecan-1 and both N-94 and N-94/C-6, and explore CRISPR/Cas9 mediator hits to expand our understanding of lacritin signaling mechanisms. Our long-term goal is to harness this information towards the effective and lasting treatment of dry eye disease. University of Virginia Charlottesville Virginia University of California San Francisco San Francisco California


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 = $424,856 )
2025	2025	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	001	5	9/19/2025	NON-COMPETING CONTINUATION	$424,856
2025	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	000	4	11/1/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $424,856

Issue Date FY: 2024 ( Subtotal = $499,831 )
2024	2024	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 EMMET ST N	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	000	4	7/31/2024	NON-COMPETING CONTINUATION	$499,831
														Subtotal = $499,831

Issue Date FY: 2023 ( Subtotal = $499,831 )
2023	2023	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	000	3	8/9/2023	NON-COMPETING CONTINUATION	$499,831
														Subtotal = $499,831

Issue Date FY: 2022 ( Subtotal = $484,836 )
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	000	2	7/15/2022	NON-COMPETING CONTINUATION	$484,836
2022	2022	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	001	2	7/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $484,836

Issue Date FY: 2021 ( Subtotal = $515,206 )
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	001	1	9/15/2021	NEW	$157,335
2021	2021	RECTOR & VISITORS OF THE UNIVERSITY OF VIRGINIA	1001 N EMMET ST	CHARLOTTESVILLE	VA	22903	CHARLOTTESVILLE CITY	USA	Vision Research	000	1	8/30/2021	NEW	$357,871
														Subtotal = $515,206

Grand Total All Awards = $2,424,560

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Lacritin Regulation of Homeostasis and Ocular Surface Health

Award Number: R01EY032956

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2021

PERIOD OF PERFORMANCE END DATE: 07/31/2026

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