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Pathogenesis of Bacterial Keratitis

Award Number: R01EY014362
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 04/01/2003
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Pathogenesis of Bacterial Keratitis - Abstract The pathogenic bacteria Pseudomonas aeruginosa is a major cause of blinding corneal infections in the USA and worldwide. This includes a recent outbreak of drug resistant P. aeruginosa keratitis in contaminated eyedrops that caused keratitis in 68 patients from 16 US states and resulted in 3 deaths and 8 enucleations. Our earlier studies supported by this grant demonstrated that P. aeruginosa virulence in infected corneas is due to expression of the Type III secretion system, which comprises a needle structure that injects exoenzymes directly into the host cell cytosol. Our recent data show that using either NLRP3-/- mice or the NLRP3 small molecule inhibitor MCC950, P. aeruginosa ExoS ADP ribosyl transferase (ADPRT) selectively licenses NLRP3 inflammasome usage in neutrophils (where macrophages use the NLRC4 inflammasome) for IL-1β processing and secretion, and importantly that NLRP3 is required for effective bacterial killing in infected corneas that can be blocked with the small molecule inhibitor MCC950. Proposed studies in Aim 1 will examine the early events in NLRP3 activation in neutrophils, including a role for NEK7 and HDAC6, which will also be examined during infection. Aim 2 will use an HEK293 based expression system to produce mg levels of NLRP3 that can used to identifying NLRP3 domains and specific arginine residues that are targeted by ExoS ADPRT. Aim 3 will examine cell death pathways in corneal epithelial cells and neutrophils infected with P. aeruginosa expressing the Type II secretion protein ToxA and determine if there is a role for NLRP1 pyroptotic cell death and in corneal infections. Results of these proposed studies will identify novel targets for immune intervention in this blinding infection.


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 = $676,812 )
2026	2026	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	22	6/10/2026	NON-COMPETING CONTINUATION	$676,812
														Subtotal = $676,812

Issue Date FY: 2025 ( Subtotal = $676,812 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	21	5/29/2025	NON-COMPETING CONTINUATION	$676,812
2025	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	19	2/24/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $676,812

Issue Date FY: 2024 ( Subtotal = $705,516 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	20	5/22/2024	COMPETING CONTINUATION	$705,516
2024	2022	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	19	5/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $705,516

Issue Date FY: 2022 ( Subtotal = $397,702 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	19	7/5/2022	NON-COMPETING CONTINUATION	$397,702
														Subtotal = $397,702

Issue Date FY: 2021 ( Subtotal = $397,701 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	18	6/7/2021	NON-COMPETING CONTINUATION	$397,701
														Subtotal = $397,701

Issue Date FY: 2020 ( Subtotal = $410,000 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	17	7/23/2020	NON-COMPETING CONTINUATION	$410,000
														Subtotal = $410,000

Issue Date FY: 2019 ( Subtotal = $403,494 )
2019	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	16	9/17/2019	COMPETING CONTINUATION	$408,875
2019	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	15	6/13/2019	NON-COMPETING CONTINUATION	-$5,381
														Subtotal = $403,494

Issue Date FY: 2018 ( Subtotal = $386,250 )
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	15	5/7/2018	NON-COMPETING CONTINUATION	$38,625
2018	2018	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	15	1/16/2018	NON-COMPETING CONTINUATION	$347,625
														Subtotal = $386,250

Issue Date FY: 2017 ( Subtotal = $386,250 )
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	14	2/8/2017	NON-COMPETING CONTINUATION	$347,625
2017	2017	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	14	7/10/2017	NON-COMPETING CONTINUATION	$38,625
														Subtotal = $386,250

Issue Date FY: 2016 ( Subtotal = $386,250 )
2016	2016	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	13	1/28/2016	NON-COMPETING CONTINUATION	$386,250
														Subtotal = $386,250

Issue Date FY: 2015 ( Subtotal = $388,325 )
2015	2015	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	11	12/22/2014	NON-COMPETING CONTINUATION	$356,625
2015	2015	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	11	2/23/2015	NON-COMPETING CONTINUATION	$31,700
2015	2015	UNIVERSITY OF CALIFORNIA, IRVINE	2301 BERKELEY PLACE	IRVINE	CA	92697	ORANGE	USA	Vision Research	003	12	7/30/2015	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$388,325
2015	2015	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	002	11	7/30/2015	NON-COMPETING CONTINUATION	-$388,325
														Subtotal = $388,325

Issue Date FY: 2014 ( Subtotal = $396,250 )
2014	2014	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	10	12/30/2013	COMPETING CONTINUATION	$396,250
														Subtotal = $396,250

Issue Date FY: 2012 ( Subtotal = $373,032 )
2012	2012	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	9	8/6/2012	NON-COMPETING CONTINUATION	$373,032
														Subtotal = $373,032

Issue Date FY: 2011 ( Subtotal = $373,032 )
2011	2011	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	8	7/29/2011	NON-COMPETING CONTINUATION	$373,032
														Subtotal = $373,032

Issue Date FY: 2010 ( Subtotal = $388,575 )
2010	2010	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	7	8/3/2010	NON-COMPETING CONTINUATION	$388,575
														Subtotal = $388,575

Issue Date FY: 2009 ( Subtotal = $392,500 )
2009	2009	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	6	7/20/2009	COMPETING CONTINUATION	$392,500
														Subtotal = $392,500

Issue Date FY: 2007 ( Subtotal = $297,135 )
2007	2007	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	5	4/4/2007	NON-COMPETING CONTINUATION	$297,135
														Subtotal = $297,135

Issue Date FY: 2006 ( Subtotal = $298,809 )
2006	2006	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	4	3/14/2006	NON-COMPETING CONTINUATION	$298,809
														Subtotal = $298,809

Issue Date FY: 2005 ( Subtotal = $306,000 )
2005	2005	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	3	4/4/2005	NON-COMPETING CONTINUATION	$306,000
														Subtotal = $306,000

Issue Date FY: 2004 ( Subtotal = $306,000 )
2004	2004	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	2	2/16/2004	NON-COMPETING CONTINUATION	$306,000
														Subtotal = $306,000

Issue Date FY: 2003 ( Subtotal = $344,250 )
2003	2003	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	1		NEW	$344,250
														Subtotal = $344,250

Grand Total All Awards = $8,690,695

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Award Information

Pathogenesis of Bacterial Keratitis

Award Number: R01EY014362

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 04/01/2003

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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