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Immunopathogenesis of Adenovirus Keratitis

Award Number: R01EY013124
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2001
PERIOD OF PERFORMANCE END DATE: 01/31/2027

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Immunopathogenesis of Adenovirus Keratitis - PROJECT SUMMARY Conjunctivitis, a common ocular condition with a range of etiologies, is highly prevalent, affecting approximately 6 million people annually in the United States, accounting for 1% of all primary care office visits, and costing 430 million USD annually. Viruses are responsible for ~ 80% of conjunctivitis cases, and human adenoviruses (HAdVs) are implicated in up to 65%. A particularly severe variant of adenoviral conjunctivitis, epidemic keratoconjunctivitis (EKC) is caused principally by viruses within human adenovirus species D (HAdV-D), for example the highly virulent adenovirus type 37. The clinical manifestations of EKC include severe membranous conjunctivitis and epithelial keratitis, followed by delayed onset of multifocal subepithelial (stromal) corneal infiltrates that cause light sensitivity and reduced vision and can persist or recur for months to years after the acute infection. We have shown previously that acute HAdV-D infection of human keratocytes induces intracellular signaling and robust expression of neutrophil and monocyte chemokines, and that physical components of the adenovirus (viral capsid and DNA) initiate molecular pattern responses in the corneal stroma. However, why adenovirus keratitis can be chronic and recurrent when the infection has resolved and the adenovirus is no longer present has not been previously studied. The specific aims of this proposal are to test the hypotheses that 1) the post EKC cornea expresses a unique array of pro-inflammatory mediators, 2) the post EKC cornea retains innate immune cells with a chronically altered transcriptome, and 3) long- lasting pro-inflammatory changes in the post EKC cornea can be mitigated by epigenetic modifying agents. We will study the cornea in our adenovirus mouse keratitis model after resolution of the infection, using protein arrays and immuno-microscopy to elucidate the pro-inflammatory mediators responsible for chronic adenovirus keratitis, flow cytometry and single cell RNA-seq to determine infiltrating cellular phenotypes and individual cell type transcriptomes, and single cell ATAC-seq to determine changes in cellular chromatin of resident keratocytes and infiltrating cells. Finally, we will apply known modifying agents of cellular chromatin in an attempt to prevent, reduce, or reverse pro- inflammatory mediator expression and pathologic innate immune cell phenotypes in chronic adenovirus keratitis. These studies are designed to take us closer to our goal of effective information-based therapies against HAdV eye infections. EKC is a common affliction, and the proposed study addresses a major public health concern.


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 = $319,677 )
2025	2025	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Vision Research	000	24	1/15/2025	NON-COMPETING CONTINUATION	$319,677
														Subtotal = $319,677

Issue Date FY: 2024 ( Subtotal = $318,602 )
2024	2024	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Vision Research	000	23	1/24/2024	NON-COMPETING CONTINUATION	$318,602
														Subtotal = $318,602

Issue Date FY: 2023 ( Subtotal = $318,602 )
2023	2023	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Vision Research	000	22	1/27/2023	NON-COMPETING CONTINUATION	$318,602
2023	2022	UNIVERSITY OF NEW MEXICO	1 UNIVERSITY OF NEW MEXICO	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Vision Research	002	21	7/2/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$5,178
2023	2022	MASSACHUSETTS EYE AND EAR INFIRMARY	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	20	7/2/2023	COMPETING CONTINUATION	-$5,178
														Subtotal = $318,602

Issue Date FY: 2022 ( Subtotal = $424,999 )
2022	2022	UNIVERSITY OF NEW MEXICO	2500 MARBLE DR NE	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Vision Research	004	21	9/21/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$187,180
2022	2022	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	003	20	9/21/2022	COMPETING CONTINUATION	-$187,181
2022	2022	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	20	1/26/2022	COMPETING CONTINUATION	$425,000
2022	2020	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	19	6/15/2022	NON-COMPETING CONTINUATION	$0
2022	2020	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	19	1/20/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $424,999

Issue Date FY: 2020 ( Subtotal = $425,000 )
2020	2020	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	19	3/19/2020	NON-COMPETING CONTINUATION	$425,000
														Subtotal = $425,000

Issue Date FY: 2019 ( Subtotal = $425,000 )
2019	2019	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	18	3/14/2019	NON-COMPETING CONTINUATION	$425,000
														Subtotal = $425,000

Issue Date FY: 2018 ( Subtotal = $425,000 )
2018	2018	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	17	3/20/2018	NON-COMPETING CONTINUATION	$382,500
2018	2018	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	003	17	5/24/2018	NON-COMPETING CONTINUATION	$42,500
2018	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	16	11/30/2017	COMPETING CONTINUATION	$59,065
2018	2015	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	15	11/30/2017	NON-COMPETING CONTINUATION	-$59,065
														Subtotal = $425,000

Issue Date FY: 2017 ( Subtotal = $425,000 )
2017	2017	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	16	3/16/2017	COMPETING CONTINUATION	$425,000
2017	2015	MASSACHUSETTS EYE AND EAR INFIRMARY & PHYSICIAN STAFF, INC.	243 CHARLES ST	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	15	3/13/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $425,000

Issue Date FY: 2015 ( Subtotal = $416,398 )
2015	2015	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	15	6/8/2015	NON-COMPETING CONTINUATION	$416,398
														Subtotal = $416,398

Issue Date FY: 2014 ( Subtotal = $416,399 )
2014	2014	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	14	6/10/2014	NON-COMPETING CONTINUATION	$416,399
														Subtotal = $416,399

Issue Date FY: 2013 ( Subtotal = $403,652 )
2013	2013	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	13	6/10/2013	NON-COMPETING CONTINUATION	$403,652
														Subtotal = $403,652

Issue Date FY: 2012 ( Subtotal = $389,781 )
2012	2012	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	12	6/11/2012	NON-COMPETING CONTINUATION	$389,781
														Subtotal = $389,781

Issue Date FY: 2011 ( Subtotal = $392,500 )
2011	2011	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	11	9/2/2011	COMPETING CONTINUATION	$392,500
2011	2010	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	10	8/31/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $392,500

Issue Date FY: 2010 ( Subtotal = $468,852 )
2010	2010	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	001	10	6/30/2010	NON-COMPETING CONTINUATION	$468,852
2010	2009	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	000	9	3/2/2010	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $468,852

Issue Date FY: 2009 ( Subtotal = $2,008,138 )
2009	2009	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	002	9	9/3/2009	SUPPLEMENT FOR EXPANSION	$192,597
2009	2009	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Trans-NIH Recovery Act Research Support	001	9	9/30/2009	SUPPLEMENT FOR EXPANSION	$1,350,351
2009	2009	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	9	6/22/2009	NON-COMPETING CONTINUATION	$465,190
														Subtotal = $2,008,138

Issue Date FY: 2008 ( Subtotal = $447,893 )
2008	2008	MASSACHUSETTS EYE & EAR INFIRMARY, OFF OF RES ADMIN	243 CHARLES STREET	BOSTON	MA	02114	SUFFOLK	USA	Vision Research	000	8	7/21/2008	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$447,893
														Subtotal = $447,893

Issue Date FY: 2007 ( Subtotal = $446,569 )
2007	2007	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	7	8/27/2007	NON-COMPETING CONTINUATION	$446,569
														Subtotal = $446,569

Issue Date FY: 2006 ( Subtotal = $431,629 )
2006	2006	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	6	8/21/2006	COMPETING CONTINUATION	$431,629
														Subtotal = $431,629

Grand Total All Awards = $10,482,077

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Immunopathogenesis of Adenovirus Keratitis

Award Number: R01EY013124

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2001

PERIOD OF PERFORMANCE END DATE: 01/31/2027

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