# Unfolded Protein Response in Eye Development and Disease

> **NIH NIH R01** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2020 · $421,657

## Abstract

Project Summary
The Unfolded Protein Response (UPR) refers to intracellular signaling pathways that are activated in response to
endoplasmic reticulum (ER) stress. Efficient UPR signaling can help suppress diseases caused by misfolded
proteins in the ER, such as those caused by mutant rhodopsins that underlie Retinitis Pigmentosa (RP).
Conversely, defective UPR can lead to the dysfunction of certain cell types that are normally under physiological
ER stress. The long term goal of this project is to understand the precise role and regulatory mechanisms of UPR
in eye development and retinal degeneration. The current understanding of the UPR centers around ER stress
sensor proteins that include IRE1 (Inositol Requiring 1), which detects misfolded peptides through a luminal
peptide binding domain and initiates a branch of UPR signaling. In this proposal, we propose experiments that
may change our basic understandings of UPR and its role in eye development and disease. Specifically in Aim 1,
we plan to challenge the idea that IRE1-mediated UPR’s primary physiological role is to respond to misfolded
peptides in the ER. IRE1 is required for normal Drosophila eye development, but contradicting the widely
accepted role of IRE1 in detecting and responding to misfolded peptides, our preliminary studies indicate that
IRE1’s developmental role is independent of its luminal domain that senses misfolded peptides. Based on this, I
propose plans to test the idea that IRE1’s main role in the developing eye is not to help cells respond to unfolded
proteins, but instead, to respond to other sources of physiological stress. In Aims 2 and 3, we will characterize a
previously unrecognized UPR signaling branch. Specifically, we will test the hypothesis that retinoids, which are
conjugated to properly folded rhodopsins to serve as chromophores, act as signaling molecules when released
from misfolded rhodopsins to mediate Rhodopsin-1-specific UPR signaling. The possibility that retinoids actively
regulate gene expression in Drosophila has thus far been largely overlooked. Our hypothesis is based in part on
our unexpected preliminary data that retinoids can induce gene expression in Drosophila, and two such inducible
genes highroad and fabp are involved in degrading mutant Drosophila Rhodopsin-1 alleles that are similar in
their nature with human rhodopsin mutants that underlie RP. As part of this effort, we propose in Aim 2 to
characterize the role of FABP, a Drosophila homolog of Cellular Retinoic Acid Binding Proteins, in
retinoid-mediated gene expression control and retinal degeneration in the RP model. In Aim 3, we propose to
identify the transcription factor that mediates retinoid signaling in Drosophila photoreceptors, and determine its
role in mutant rhodopsin degradation and retinal degeneration. A successful outcome of these plans will
significantly change our current understanding of UPR’s physiological role, and may contribute to the
development of therapeutic ...

## Key facts

- **NIH application ID:** 9933924
- **Project number:** 5R01EY020866-10
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** HYUNG D RYOO
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $421,657
- **Award type:** 5
- **Project period:** 2010-08-01 → 2022-05-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9933924

## Citation

> US National Institutes of Health, RePORTER application 9933924, Unfolded Protein Response in Eye Development and Disease (5R01EY020866-10). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9933924. Licensed CC0.

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