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The Role of gK in HSV-1 Induced Corneal Scarring

Award Number: R01EY013615
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/09/2002
PERIOD OF PERFORMANCE END DATE: 03/31/2025

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The Role of gK in HSV-1 Induced Corneal Scarring - ABSTRACT The goal of this renewal application is to determine if blocking the mechanisms involved in intracellular HSV-1 gK processing and trafficking to the cell surface reduces virus replication and infectivity and thereby corneal scarring (CS). It is well established that CS is the result of virus-induced immune responses although the identity of the pathogenic responses is controversial. Similarly, the HSV-1 gene(s) involved in eye disease is not yet known although several lines of evidence indicate that gK plays a crucial role in replication and infectivity as exemplified by the inability of HSV-1 gK mutants to grow in cells lacking gK as they fail to acquire a cytoplasmic envelope efficiently and are unable to infect and establish latency in neurons. Our progress during the current funding period has provided novel insights into potential mechanisms of regulating gK expression in conjunction with its binding to UL20 and suggest that SPP may define the extent of primary infections, latency-reactivation, and CS. We have now shown that: (1) Binding of gK to SPP and UL20 to GODZ is required for HSV-1-induced CS; and (2) Amino acids 31-46 of gK are involved in binding to SPP, aa 280-295 of gK bind to UL20, and aa 51-65 of UL20 bind to GODZ (preliminary studies). These observations suggest mechanisms that may reveal innovative potential therapeutic targets to prevent ocular HSV-1 infection and CS. Based on our data, we suggest a hypothetical model of the mechanisms underlying the pathogenic effects of gK. In this model, the pathogenic effects of gK during primary ocular infection are mediated by two different, but interrelated, mechanisms in which (i) gK binds to SPP in the endoplasmic reticulum (ER) and UL20 in the Golgi, leading to increased virus replication and cell surface expression of gK that is necessary for gK-induced CS and increased eye disease; and (ii) UL20 also binds to GODZ in the Golgi, which is required for cell surface expression of gK. Thus, potential therapies might include blocking of gK-SPP, gK-UL20, UL20- GODZ interactions, or a combination of these strategies. We will test a hypothetical model in which the pathogenic effects of gK during primary ocular infection is mediated by three inter-related mechanisms: (i) gK binds to SPP leading to higher levels of virus replication; (ii) gK binds to UL20, which is required for the cell surface expression of gK; and (iii) UL20 binds to GODZ, which is required for UL20 palmitoylation and thus its proper binding to gK. We will: (1) Test the hypothesis that complete absence of SPP in peripheral nerves or eyes will reduce primary HSV-1 infection, latency-reactivation, and eye disease in ocularly infected mice compared with tamoxifen-inducible SPP depleted mice; and (2) Identifying effective therapeutic targets to reduce HSV-1 primary infection, latency-reactivation, and thus HSV-1-induced CS. CLINICAL SIGNIFICANCE: HSV-1-induced CS can lead to blindness and is the leading cause of infectious blindness in developed countries but there is no FDA approved drug for its treatment. The proposed studies represent an entirely novel approach to the development of effective strategies for the prevention and treatment of this disease.


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: 2024 ( Subtotal = $417,500 )
2024	2024	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	000	19	2/29/2024	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2023 ( Subtotal = $417,500 )
2023	2023	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	WEST HOLLYWOOD	CA	90048	LOS ANGELES	USA	Vision Research	000	18	4/12/2023	NON-COMPETING CONTINUATION	$417,500
														Subtotal = $417,500

Issue Date FY: 2022 ( Subtotal = $404,975 )
2022	2022	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	17	3/23/2022	NON-COMPETING CONTINUATION	$404,975
														Subtotal = $404,975

Issue Date FY: 2021 ( Subtotal = $417,500 )
2021	2021	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	16	3/26/2021	COMPETING CONTINUATION	$417,500
2021	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	15	9/18/2021	NON-COMPETING CONTINUATION	$0
														Subtotal = $417,500

Issue Date FY: 2019 ( Subtotal = $437,500 )
2019	2019	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	15	3/25/2019	NON-COMPETING CONTINUATION	$437,500
														Subtotal = $437,500

Issue Date FY: 2018 ( Subtotal = $437,500 )
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	14	3/8/2018	NON-COMPETING CONTINUATION	$393,750
2018	2018	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	14	5/22/2018	NON-COMPETING CONTINUATION	$43,750
														Subtotal = $437,500

Issue Date FY: 2017 ( Subtotal = $437,500 )
2017	2017	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	13	7/24/2017	NON-COMPETING CONTINUATION	$43,750
2017	2017	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	13	3/20/2017	NON-COMPETING CONTINUATION	$393,750
														Subtotal = $437,500

Issue Date FY: 2016 ( Subtotal = $437,500 )
2016	2016	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	12	3/16/2016	COMPETING CONTINUATION	$437,500
2016	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	11	3/11/2016	NON-COMPETING CONTINUATION	$0
														Subtotal = $437,500

Issue Date FY: 2015 ( Subtotal = $409,150 )
2015	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	11	2/23/2015	NON-COMPETING CONTINUATION	$33,400
2015	2015	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	11	12/22/2014	NON-COMPETING CONTINUATION	$375,750
														Subtotal = $409,150

Issue Date FY: 2014 ( Subtotal = $409,150 )
2014	2014	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	10	11/14/2013	NON-COMPETING CONTINUATION	$375,750
2014	2014	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	10	3/11/2014	NON-COMPETING CONTINUATION	$33,400
														Subtotal = $409,150

Issue Date FY: 2013 ( Subtotal = $396,625 )
2013	2013	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	9	5/23/2013	NON-COMPETING CONTINUATION	$20,875
2013	2013	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	9	12/12/2012	NON-COMPETING CONTINUATION	$375,750
														Subtotal = $396,625

Issue Date FY: 2012 ( Subtotal = $417,500 )
2012	2012	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	001	8	1/1/2012	COMPETING CONTINUATION	$417,500
2012	2010	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	7	12/30/2011	NON-COMPETING CONTINUATION	$0
														Subtotal = $417,500

Issue Date FY: 2010 ( Subtotal = $361,969 )
2010	2010	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	7	4/21/2010	NON-COMPETING CONTINUATION	$361,969
														Subtotal = $361,969

Issue Date FY: 2009 ( Subtotal = $365,625 )
2009	2009	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	6	4/21/2009	NON-COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2008 ( Subtotal = $365,625 )
2008	2008	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	5	4/24/2008	COMPETING CONTINUATION	$365,625
														Subtotal = $365,625

Issue Date FY: 2005 ( Subtotal = $267,750 )
2005	2005	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	4	6/22/2005	NON-COMPETING CONTINUATION	$267,750
														Subtotal = $267,750

Issue Date FY: 2004 ( Subtotal = $267,750 )
2004	2004	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	3	6/21/2004	NON-COMPETING CONTINUATION	$267,750
														Subtotal = $267,750

Issue Date FY: 2003 ( Subtotal = $267,750 )
2003	2003	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	2	7/11/2003	NON-COMPETING CONTINUATION	$267,750
														Subtotal = $267,750

Issue Date FY: 2002 ( Subtotal = $267,750 )
2002	2002	CEDARS-SINAI MEDICAL CENTER	8700 BEVERLY BLVD, METRO 203	LOS ANGELES	CA	90048	LOS ANGELES	USA	Vision Research	000	1	9/9/2002	NEW	$267,750
														Subtotal = $267,750

Grand Total All Awards = $7,204,119

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The Role of gK in HSV-1 Induced Corneal Scarring

Award Number: R01EY013615

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/09/2002

PERIOD OF PERFORMANCE END DATE: 03/31/2025

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