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Mechanism of photoreceptor cell degeneration in animal models of retinal diseases

Award Number: R01EY010609
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/01/1995
PERIOD OF PERFORMANCE END DATE: 11/30/2025

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Mechanism of photoreceptor cell degeneration in animal models of retinal diseases - PROJECT SUMMARY Our aims are focused on advancing current knowledge on the role of peripherin 2 (Prph2), also called retinal degeneration slow (RDS), in outer segment (OS) rim and disc formation, and in understanding the pathogenic mechanisms of PRPH2-associated disease. We use state-of-the-art technologies and our novel knockin mouse models to learn 1) how different mutations in Prph2 lead to different disease phenotypes; 2) what contributes to variability among patients carrying the same mutation; 3) what role the Prph2 partner, rod outer segment membrane protein 1 (Rom1), plays in these events; and 4) how we can shift PRPH2-associated severe phenotypes to milder ones. PRPH2 mutations lead to retinal diseases ranging from retinitis pigmentosa (RP) to a variety of macular degenerations (MD) including pattern dystrophy (PD), which often associates with secondary defects in neighboring tissues such as the retinal pigment epithelium and retinal/choroidal vasculature. In spite of the scientific progress so far, a therapeutic option suitable for clinical testing has not yet been developed. This disappointing outcome is further complicated by the diverse role of Prph2 in rods versus cones, poor genotype-phenotype correlations, vast intrafamilial and interfamilial phenotypic variability, the involvement of multiple tissues in the disease process, and the need for a precise dose of Prph2 to combat the devastating effect of haploinsufficiency. Thus a thorough understanding of Prph2-associated disease mechanisms, an absolute prerequisite for the development of effective therapies, requires precise knowledge of the differential role of Prph2 in rods versus cones and the processes that link photoreceptor defects with subsequent toxic effects in other tissues. Our findings suggest that rod-targeted disease (e.g. RP) arises due to haploinsufficiency while cone-dominant diseases exhibit a more complex and variable pathology associated with gain-of-function or dominant-negative effects. However, little is known about the link between these primary defects in photoreceptors and the blinding secondary sequellae or about what causes intrafamilial phenotypic heterogeneity. For the first time we have generated mouse models that will allow us to address these questions. In addition, we have developed an outstanding team of investigators comprising recognized field leaders in photoreceptor cell biology, with researchers skilled in understanding and evaluating choroidal and retinal vasculature. Our preliminary data support the hypothesis that Rom1 is a key modifier in cases where there is significant within-mutation disease variability. Aim1 will assess the role of Syn3B interactions with Prph2/Rom1 and in OS trafficking. Aim 2 will evaluate mechanisms of diversity in Prph2-associated disease phenotype. Aim 3 will address the role of Rom1 in modulating the disease pathology of Prph2 mutations. In summary, results from this application will facilitate our understanding of the role of Prph2 in rods and cones in health and disease states. Outcomes from these studies will help direct therapeutic strategies to overcome blindness associated with PRPH2.


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 = $605,791 )
2025	2025	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Vision Research	001	28	7/23/2025	COMPETING CONTINUATION	$605,791
2025	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Vision Research	000	27	7/22/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $605,791

Issue Date FY: 2024 ( Subtotal = $508,598 )
2024	2024	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Vision Research	000	27	11/29/2023	NON-COMPETING CONTINUATION	$508,598
														Subtotal = $508,598

Issue Date FY: 2023 ( Subtotal = $623,249 )
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Vision Research	000	26	2/16/2023	NON-COMPETING CONTINUATION	$508,598
2023	2023	UNIVERSITY OF HOUSTON SYSTEM	4300 MARTIN LUTHER KING BLVD	HOUSTON	TX	77204	HARRIS	USA	Vision Research	001	26	4/12/2023	SUPPLEMENT FOR EXPANSION	$114,651
														Subtotal = $623,249

Issue Date FY: 2022 ( Subtotal = $497,608 )
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	001	25	5/4/2022	NON-COMPETING CONTINUATION	$35,911
2022	2022	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	000	25	12/2/2021	NON-COMPETING CONTINUATION	$461,697
														Subtotal = $497,608

Issue Date FY: 2021 ( Subtotal = $497,607 )
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	000	24	1/12/2021	NON-COMPETING CONTINUATION	$461,697
2021	2021	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	001	24	2/23/2021	NON-COMPETING CONTINUATION	$35,910
														Subtotal = $497,607

Issue Date FY: 2020 ( Subtotal = $539,089 )
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	001	23	12/12/2019	COMPETING CONTINUATION	$539,089
2020	2020	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	003	23	6/12/2020	COMPETING CONTINUATION	$11,793
2020	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	000	22	12/12/2019	NON-COMPETING CONTINUATION	$0
2020	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	002	22	6/12/2020	NON-COMPETING CONTINUATION	-$11,793
														Subtotal = $539,089

Issue Date FY: 2019 ( Subtotal = $376,250 )
2019	2019	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	000	22	12/11/2018	NON-COMPETING CONTINUATION	$376,250
														Subtotal = $376,250

Issue Date FY: 2018 ( Subtotal = $376,250 )
2018	2018	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	000	21	11/20/2017	NON-COMPETING CONTINUATION	$338,625
2018	2018	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	001	21	5/7/2018	NON-COMPETING CONTINUATION	$37,625
														Subtotal = $376,250

Issue Date FY: 2017 ( Subtotal = $376,250 )
2017	2017	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	001	20	7/3/2017	NON-COMPETING CONTINUATION	$37,625
2017	2017	UNIVERSITY OF HOUSTON SYSTEM	4800 W CALHOUN ST STE 316	HOUSTON	TX	77004	HARRIS	USA	Vision Research	000	20	11/17/2016	NON-COMPETING CONTINUATION	$338,625
														Subtotal = $376,250

Issue Date FY: 2016 ( Subtotal = $376,250 )
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	002	18	2/9/2016	NON-COMPETING CONTINUATION	-$333,000
2016	2016	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	18	11/16/2015	NON-COMPETING CONTINUATION	$333,000
2016	2016	UNIVERSITY OF HOUSTON DOWNTOWN	ONE MAIN STREET	HOUSTON	TX	77002	HARRIS	USA	Vision Research	001	19	2/9/2016	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$376,250
														Subtotal = $376,250

Issue Date FY: 2015 ( Subtotal = $420,000 )
2015	2015	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	17	12/17/2014	COMPETING CONTINUATION	$420,000
														Subtotal = $420,000

Issue Date FY: 2012 ( Subtotal = $523,943 )
2012	2012	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	16	9/11/2012	NON-COMPETING CONTINUATION	$523,943
														Subtotal = $523,943

Issue Date FY: 2011 ( Subtotal = $495,259 )
2011	2011	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	15	8/22/2011	NON-COMPETING CONTINUATION	$495,259
														Subtotal = $495,259

Issue Date FY: 2010 ( Subtotal = $498,048 )
2010	2010	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	14	8/26/2010	NON-COMPETING CONTINUATION	$498,048
														Subtotal = $498,048

Issue Date FY: 2009 ( Subtotal = $499,907 )
2009	2009	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	P.O. BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	13	8/12/2009	COMPETING CONTINUATION	$499,907
														Subtotal = $499,907

Issue Date FY: 2007 ( Subtotal = $492,695 )
2007	2007	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Family Violence Prevention and Services/Domestic Violence Shelter and Supportive Services	000	12	4/27/2007	NON-COMPETING CONTINUATION	$492,695
														Subtotal = $492,695

Issue Date FY: 2006 ( Subtotal = $481,035 )
2006	2006	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Family Violence Prevention and Services/Domestic Violence Shelter and Supportive Services	000	11	5/29/2006	NON-COMPETING CONTINUATION	$481,035
														Subtotal = $481,035

Issue Date FY: 2005 ( Subtotal = $478,263 )
2005	2005	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Family Violence Prevention and Services/Domestic Violence Shelter and Supportive Services	000	10	4/21/2005	COMPETING CONTINUATION	$478,263
														Subtotal = $478,263

Issue Date FY: 2003 ( Subtotal = $535,962 )
2003	2003	UNIVERSITY OF OKLAHOMA HEALTH SCIENCES CENTER	POST OFFICE BOX 26901	OKLAHOMA CITY	OK	73190	OKLAHOMA	USA	Vision Research	000	9		NON-COMPETING CONTINUATION	$535,962
														Subtotal = $535,962

Issue Date FY: 2002 ( Subtotal = $482,023 ) (Continued on the next page)
Grand Total All Awards = $10,790,293

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Mechanism of photoreceptor cell degeneration in animal models of retinal diseases

Award Number: R01EY010609

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/01/1995

PERIOD OF PERFORMANCE END DATE: 11/30/2025

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