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Cellular and Genetic Defects in Keratoconus

Award Number: R01EY026104
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/10/2016
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Cellular and Genetic Defects in Keratoconus - Keratoconus (KC), a common corneal dystrophy that affects young people, causes progressive thinning, scarring and loss of corneal shape, which can ultimately lead to loss of vision. Crosslinking of collagens in the cornea can stiffen and delay its weakening, but severe cases require corneal transplantation. Although KC has a strong genetic component, its etiology is complex, polygenic and multifactorial. There is an urgent need to understand its etiology for developing early diagnosis and treatment strategies for KC. To address this, our competitive renewal application focuses on identifying cellular defects, biomarkers and the genetic causes of KC. Beyond obvious familial KC, the vast majority are isolated where disease likely results from rare pathogenic coding sequence variants and genome-wide common noncoding variants that increase one's susceptibility. Elucidating the underlying genetic defects in these “isolated KC” requires a range of biological evidence. Our recent studies and preliminary data provide this biological foundation for the current proposal. First, by whole- exome sequencing of KC families, we identified rare pathogenic variants in genes related to cell stress, cytoskeleton and extracellular matrix (ECM), which are now prioritized as candidate genes and networks for the isolated KC studies. Second, our transcriptomic and proteomic characterizations of KC and control donor corneas identified significant dysregulation in the NRF2-antioxidant program that is crucial for corneal cell survival and its functions. Finally, we developed corneal cell culture models that mimic key KC features, from oxidative stress to ECM insufficiency, and assays to measure these. We further developed the first cornea organoids from human induced pluripotent stem cells that will allow functional studies of genes and therapeutic agents in a physiological, cornea-like setting and in organoid-derived epithelial and stromal cell cultures. Importantly, this approach will yield cell culture disease models from genetically defined patient blood cells. These cell culture disease surrogates are particularly important, as there are no animal models that can capture the polygenic complexity of KC. In Aim 1 we will assess potential NRF2-regulated antioxidants as tear fluid biomarkers for KC, and investigate this network in corneal cell cultures. In Aim 2 we will identify rare pathogenic variants and common noncoding variants that increase disease susceptibility in isolated KC cases using the 1000Genome and the UK Biobank databases as controls. In Aim 3 we will functionally test the concept that a rare pathogenic variant (e.g., our published c.G12982A HSPG2), will cause cellular disease surrogates when CRISPR-edited into cells derived from KC individuals with high polygenic and not controls with low polygenic scores. Our findings will lead to potential anti-oxidant biomarkers, development of NRF2- activators for KC treatments, genetically defined KC cell culture models and insights into the complex genetic architecture of KC. Our studies are highly relevant to the goals of the NEI in understanding the complex genetics of eye diseases, treatments and reversing vision loss.


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: 2026 ( Subtotal = $618,407 )
2026	2026	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Vision Research	000	7	2/3/2026	NON-COMPETING CONTINUATION	$618,407
														Subtotal = $618,407

Issue Date FY: 2025 ( Subtotal = $618,407 )
2025	2025	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Vision Research	000	6	1/23/2025	NON-COMPETING CONTINUATION	$618,407
														Subtotal = $618,407

Issue Date FY: 2024 ( Subtotal = $615,948 )
2024	2024	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Vision Research	000	5	1/30/2024	NON-COMPETING CONTINUATION	$615,948
														Subtotal = $615,948

Issue Date FY: 2023 ( Subtotal = $625,118 )
2023	2023	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Vision Research	000	4	2/27/2023	COMPETING CONTINUATION	$625,118
														Subtotal = $625,118

Issue Date FY: 2021 ( Subtotal = -$1 )
2021	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Vision Research	000	3	1/14/2021	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1
														Subtotal = -$1

Issue Date FY: 2019 ( Subtotal = $0 )
2019	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Vision Research	001	3	11/6/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$518,079
2019	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Vision Research	000	2	11/6/2018	NON-COMPETING CONTINUATION	-$518,079
														Subtotal = $0

Issue Date FY: 2018 ( Subtotal = $606,483 )
2018	2018	NEW YORK UNIVERSITY	550 1ST AVE	NEW YORK	NY	10016	NEW YORK	USA	Vision Research	001	3	7/13/2018	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$606,483
2018	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Vision Research	000	2	7/13/2018	NON-COMPETING CONTINUATION	$0
														Subtotal = $606,483

Issue Date FY: 2017 ( Subtotal = $579,647 )
2017	2017	JOHNS HOPKINS UNIVERSITY, THE	3400 N CHARLES ST	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Vision Research	000	2	6/15/2017	NON-COMPETING CONTINUATION	$579,647
														Subtotal = $579,647

Issue Date FY: 2016 ( Subtotal = $579,647 )
2016	2016	JOHNS HOPKINS UNIVERSITY	1101 E 33RD STREET, STE-C-210	BALTIMORE	MD	21218	BALTIMORE CITY	USA	Vision Research	000	1	5/31/2016	NEW	$579,647
														Subtotal = $579,647

Grand Total All Awards = $4,243,656

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Cellular and Genetic Defects in Keratoconus

Award Number: R01EY026104

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/10/2016

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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