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Molecular mechanisms of translational control in mice with inherited retinal degeneration

Award Number: R01EY027763
ORGANIZATION: NATIONAL EYE INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 02/01/2018
PERIOD OF PERFORMANCE END DATE: 01/31/2024

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Molecular mechanisms of translational control in mice with inherited retinal degeneration - Inherited retinal degeneration (IRD) diseases are a clinically and genetically diverse group of retinal dystrophies including Leber congenital amaurosis (LCA) and autosomal dominant retinitis pigmentosa (ADRP). Despite significant progress in the basic science and clinical aspects of many retinopathies, the cellular mechanisms responsible for inherited vision loss require further investigation, and effective therapies are still under development. Therefore, we focused on the elucidation of the IRD mechanism and the development of therapeutic strategies. In particular, we address the role of translational attenuation in retinal pathogenesis of mice-mimicking human ADRP and LCA and propose therapeutic approaches based on the restoration of protein synthesis in affected photoreceptors. The proposal is supported by strong scientific premises created by our published and preliminary data, as well as the works of others. They suggest that mice with IRD experience persistent activation of the unfolded protein response (UPR) and translational attenuation in the retinas. In addition, our preliminary data demonstrate that PERK (protein kinase R [PKR]-like endoplasmic reticulum kinase) UPR arm is responsible for the sustained translational suppression in stressed photoreceptors. To support this, we will investigate three PERK-induced targets that independently regulate the consensual work of translational machinery. First, we plan to evaluate the impact of translational attenuation on retinal degeneration provided by phosphorylated eIF2a, a major hallmark of translational block. Second, we plan to assess the role of TRB3 in retinal degeneration by modifying its expression, thereby testing the hypothesis that TRB3 increase during IRD progression is cytotoxic, while its down-regulation enhances protein synthesis and retards IRD progression. Finally, we plan to test the hypothesis that stabilization of the 5'cap mRNA recognition complex by deactivation of eukaryotic initiation factor 4E (4E-BP), a negative translational regulator slows the onset of IRD through augmentation of protein synthesis. Genetically modified mice expressing altered levels of UPR and mRNA translation-associated markers; mice-modeling human IRD; pharmacological approaches altering levels of UPR markers; and adeno-associated viral gene delivery will be used in the study to regulate protein synthesis and explore therapeutic approaches. To our knowledge, this is the first comprehensive study of translational regulation in healthy and diseased photoreceptors. If successful, this study will not only enhance our molecular understanding of how degenerating PRs die but also create a platform for therapeutic intervention to halt IRD progression in humans. PERK pathway-targeted therapies could be used as a mutation- independent treatment for retinas experiencing chronic ER stress or as a supplemental strategy to enhance pre-existing gene replacement approaches. They would be particularly attractive for mutations in large genes that cannot be treated using conventional AAV-mediated gene therapy.


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 = $0 )
2024	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH STREET	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	5	8/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $360,113 )
2022	2022	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	5	2/3/2022	NON-COMPETING CONTINUATION	$360,113
														Subtotal = $360,113

Issue Date FY: 2021 ( Subtotal = $360,112 )
2021	2021	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	001	4	2/26/2021	NON-COMPETING CONTINUATION	$360,112
2021	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	3	1/15/2021	SUPPLEMENT FOR EXPANSION	$0
														Subtotal = $360,112

Issue Date FY: 2020 ( Subtotal = $495,770 )
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	001	3	8/28/2020	SUPPLEMENT FOR EXPANSION	$124,520
2020	2020	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	3	1/29/2020	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $495,770

Issue Date FY: 2019 ( Subtotal = $371,250 )
2019	2019	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	2	1/10/2019	NON-COMPETING CONTINUATION	$371,250
														Subtotal = $371,250

Issue Date FY: 2018 ( Subtotal = $371,250 )
2018	2018	UNIVERSITY OF ALABAMA AT BIRMINGHAM	701 S 20TH ST	BIRMINGHAM	AL	35294	JEFFERSON	USA	Vision Research	000	1	1/25/2018	NEW	$371,250
														Subtotal = $371,250

Grand Total All Awards = $1,958,495

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Molecular mechanisms of translational control in mice with inherited retinal degeneration

Award Number: R01EY027763

ORGANIZATION: NATIONAL EYE INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 02/01/2018

PERIOD OF PERFORMANCE END DATE: 01/31/2024

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