# Molecular mechanisms of translational control in mice with inherited retinal degeneration

> **NIH NIH R01** · UNIVERSITY OF ALABAMA AT BIRMINGHAM · 2020 · $371,250

## Abstract

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...

## Key facts

- **NIH application ID:** 9849280
- **Project number:** 5R01EY027763-03
- **Recipient organization:** UNIVERSITY OF ALABAMA AT BIRMINGHAM
- **Principal Investigator:** Marina Gorbatyuk
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $371,250
- **Award type:** 5
- **Project period:** 2018-02-01 → 2023-01-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9849280

## Citation

> US National Institutes of Health, RePORTER application 9849280, Molecular mechanisms of translational control in mice with inherited retinal degeneration (5R01EY027763-03). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9849280. Licensed CC0.

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