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Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy

Award Number: R01EY022938
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 09/01/2013
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy - Diabetic retinopathy is clinically defined as a disease of the retinal microvasculature, and most research on its pathogenesis to date has focused on molecular and metabolic defects within the blood vessel cells themselves. In recent years, we have provided evidence that cells in the outer retina play a critical role the development of diabetic retinopathy. The current application will investigate the hypothesis that visual cycle activity plays a key role in initiation of the degenerative vascular lesions in early stages of diabetic retinopathy, and does this by increasing oxidative stress and inflammation within rod photoreceptors. Ultimately, the stressed photoreceptors release soluble factors (including cytokines) that damage the vasculature secondary to activating circulation leukocytes. Thus, the central hypothesis of our proposal is that hyperglycemia or other abnormalities that stress photoreceptors (such as rhodopsin mutants) lead to generation superoxide and other reactive products, and that these abnormalities initiate the structural and functional changes of the microvasculature which are clinically recognized as early diabetic retinopathy. Specific Aims will be: (1) to evaluate the roles of visual cycle activity in the retinal capillary damage caused by diabetes., (2) to investigate the roles of oxidative stress and/or inflammation within photoreceptors to initiate damage to the retinal vasculature, and (3) to identify soluble factors released by photoreceptors in diabetes, and mechanism by which those factors contribute to retinal capillary damage. The research proposed in Aim 1 will use mouse models in which RPE65 and LRAT are deficient, as well as a novel inhibitor of RPE65 to assess visual cycle activity. Aim 2 will be tested using mice having (i) photoreceptor-specific knockdown of activities of NADPH oxidase activity and NF-ĸB activation. Diabetes will be induced experimentally in male and female mice. This is a highly novel and testable hypothesis that will be conducted by an experienced research team. Confirmation of retinal photoreceptor cells as contributors to retinal capillary disease in DR (and other retinal vascular diseases) will offer several novel approaches to inhibit the development of these retinopathies.


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: 2023 ( Subtotal = -$15 )
2023	2021	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	9	10/31/2022	NON-COMPETING CONTINUATION	-$15
														Subtotal = -$15

Issue Date FY: 2021 ( Subtotal = $467,301 )
2021	2021	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	9	5/24/2021	NON-COMPETING CONTINUATION	$467,301
														Subtotal = $467,301

Issue Date FY: 2020 ( Subtotal = $481,664 )
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	002	8	5/21/2020	NON-COMPETING CONTINUATION	$365,327
2020	2020	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	003	8	5/26/2020	SUPPLEMENT FOR EXPANSION	$116,337
2020	2019	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	7	11/14/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$292,986
2020	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	6	11/14/2019	NON-COMPETING CONTINUATION	-$292,986
														Subtotal = $481,664

Issue Date FY: 2019 ( Subtotal = $379,086 )
2019	2019	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	7	8/23/2019	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$379,086
2019	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	6	8/23/2019	NON-COMPETING CONTINUATION	$0
														Subtotal = $379,086

Issue Date FY: 2018 ( Subtotal = $402,102 )
2018	2018	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	002	6	6/5/2018	NON-COMPETING CONTINUATION	$402,102
2018	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	5	2/12/2018	COMPETING CONTINUATION	$117,762
2018	2016	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	4	2/12/2018	EXTENSION WITH OR WITHOUT FUNDS	-$117,762
														Subtotal = $402,102

Issue Date FY: 2017 ( Subtotal = $402,102 )
2017	2017	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	001	5	8/24/2017	COMPETING CONTINUATION	$402,102
2017	2015	CASE WESTERN RESERVE UNIVERSITY	10900 EUCLID AVE	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	3	2/6/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $402,102

Issue Date FY: 2016 ( Subtotal = $396,250 )
2016	2016	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	4	7/22/2016	EXTENSION WITH OR WITHOUT FUNDS	$396,250
														Subtotal = $396,250

Issue Date FY: 2015 ( Subtotal = $388,325 )
2015	2015	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	3	7/27/2015	NON-COMPETING CONTINUATION	$388,325
														Subtotal = $388,325

Issue Date FY: 2014 ( Subtotal = $388,325 )
2014	2014	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	2	7/21/2014	NON-COMPETING CONTINUATION	$388,325
														Subtotal = $388,325

Issue Date FY: 2013 ( Subtotal = $396,250 )
2013	2013	CASE WESTERN RESERVE UNIVERSITY	2040 ADELBERT ROAD	CLEVELAND	OH	44106	CUYAHOGA	USA	Vision Research	000	1	8/2/2013	NEW	$396,250
														Subtotal = $396,250

Grand Total All Awards = $3,701,390

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Role of Photoreceptors in the Pathogenesis of Diabetic Retinopathy

Award Number: R01EY022938

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 09/01/2013

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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