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Formation of Retinyl-Opsins by Retinyl Formate as Molecular Shades Against Light-Induced Retinal Damage

Award Number: F30EY033659
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 01/24/2022
PERIOD OF PERFORMANCE END DATE: 01/23/2026

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Formation of Retinyl-Opsins by Retinyl Formate as Molecular Shades Against Light-Induced Retinal Damage - Project Summary/Abstract Stargardt disease (STGD1) is the most common form of inherited juvenile macular degeneration. STGD1 is caused by autosomal recessive mutations in the ABCA4 gene, which encodes a membrane transporter that removes all-trans-retinals (atRALs) from photoreceptors as part of the retinoid cycle. Free atRALs or their bisretinoid condensation products promote photo-oxidative damage to the macula as seen in STGD1. The same atRAL-mediated damage can also be seen in age-related macular degeneration (AMD), which is expected to affect at least 18 million Americans by 2050. The production of atRAL starts at the level of opsin proteins, which reside within photoreceptor outer segment disc membranes. Light is captured by opsin- chromophore complexes, or visual pigments, causing their native bound chromophore, 11-cis-retinal (11cRAL), to be converted to atRAL and forming activated opsins. These activated opsins initiate phototransduction and are eventually spontaneously hydrolyzed to apo-opsin and atRAL. Exposure to intense light causes photoreceptor overstimulation and dangerously high levels of atRAL, potentially leading to photoreceptor damage and loss. Recently, a chromophore analogue, retinyl formate (RF), was found to irreversibly bind apo- opsin and form retinyl-opsins that can no longer form visual pigments with 11cRAL. These retinyl-opsins also absorb light outside the visible light spectrum and do not subsequently release atRAL upon light absorption. Thus, RF can potentially reduce the proportion of visual pigments in the retina and thereby reduce the atRAL burden during periods of intense light exposure. Therefore, I hypothesize that RF can serve as a molecular shade at the opsin level, providing long-lasting protection to photoreceptors from light-induced damage. In this proposal, I will characterize the site of the retinyl modification on opsin by RF, distinguishing whether RF binding is competitive or allosteric with 11cRAL. I will determine if and how retinyl-opsins also could initiate the phototransduction cascade. To investigate its applicability to a pre-clinical model, I will study whether RF treatment of an STGD1 mouse model provides neuroprotection to photoreceptors against intense light exposure via formation of retinyl-opsins and reduction of retinal atRAL and determine the relative proportion of retinyl-opsins and remaining natural visual pigments. This work thus serves as a proof-of-concept approach to determining whether disabling a proportion of opsins with an irreversible inhibitor of visual pigment formation could prevent light-induced damage to photoreceptors, and point to the development of future therapeutics and interventions for STGD1 and AMD.


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 = $53,974 )
2025	2025	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	4	12/13/2024	NON-COMPETING CONTINUATION	$53,974
														Subtotal = $53,974

Issue Date FY: 2024 ( Subtotal = $53,974 )
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	3	1/17/2024	NON-COMPETING CONTINUATION	$52,694
2024	2024	UNIVERSITY OF CALIFORNIA IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	3	6/7/2024	NON-COMPETING CONTINUATION	$1,280
														Subtotal = $53,974

Issue Date FY: 2023 ( Subtotal = $43,836 )
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	000	2	1/4/2023	NON-COMPETING CONTINUATION	$42,894
2023	2023	UNIVERSITY OF CALIFORNIA, IRVINE	160 ALDRICH HALL	IRVINE	CA	92697	ORANGE	USA	Vision Research	001	2	3/8/2023	NON-COMPETING CONTINUATION	$942
														Subtotal = $43,836

Issue Date FY: 2022 ( Subtotal = $42,207 )
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	000	1	1/24/2022	NEW	$41,491
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	002	1	5/6/2022	NEW	$717
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	003	1	5/27/2022	NEW	-$1
2022	2022	UNIVERSITY OF CALIFORNIA, IRVINE	141 INNOVATION DR STE 250	IRVINE	CA	92617	ORANGE	USA	Vision Research	001	1	1/24/2022	NEW	$0
														Subtotal = $42,207

Grand Total All Awards = $193,991

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Formation of Retinyl-Opsins by Retinyl Formate as Molecular Shades Against Light-Induced Retinal Damage

Award Number: F30EY033659

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 01/24/2022

PERIOD OF PERFORMANCE END DATE: 01/23/2026

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