# Translational control of stress response signaling

> **NIH NIH R35** · NEW YORK UNIVERSITY SCHOOL OF MEDICINE · 2024 · $423,750

## Abstract

Project Summary
Cellular stress-responsive mechanisms are essential for cells to adapt to various environmental and
physiological conditions. The overall goal of the research program is to understand how cells regulate mRNA
translation as part of their stress adaptation process. Of particular interest is a pathway referred to as the
Integrated Stress Response (ISR), which is initiated by stress-activated eIF2a kinases that respond to several
distinct types of stress. Abnormal regulation of ISR is associated with various metabolic and neurodegenerative
diseases, including ribosomopathies caused by heterozygosity in ribosome subunit genes and Charcot Marie
Tooth Disease caused by certain tRNA synthetase mutations. The ISR signaling mechanism is intriguing
because this pathway induces stress-responsive gene transcription, and coincidentally, suppresses general
mRNA translation. ISR inhibits mRNA translation at multiple levels, including the specific inhibition of translation
initiation factors, eIF2a and eIF-4E. In addition, recent evidence indicates that ribosome stalling on mRNAs is
associated with ISR. These observations raise a fundamental question regarding how stress-responsive
transcripts overcome these multiple translational blocks, and in some cases, increase their translation as part of
ISR signaling. To address this, we propose to use the facile genetic tools of Drosophila. The ISR regulatory
mechanisms are conserved in this organism, and there are genetic mutations that serve as models for human
diseases with abnormal ISR signaling. Our preliminary genetic screen in Drosophila has identified several
poorly characterized translational regulators as factors required for ISR signaling. Building on these
observations, we will test the central hypothesis that the newly identified factors specifically mediate the
translation of stress-responsive transcripts, thereby helping those mRNAs to bypass translational blocks
imposed by ISR. We will further determine the physiological significances of the newly identified translational
regulatory mechanisms in the Drosophila models of ribosomopathies and Charcot Marie Tooth Disease. A
successful realization of the proposed plan will advance our conceptual understanding of stress-responsive
gene expression, and help develop new therapeutic strategies against diseases associated with ISR.

## Key facts

- **NIH application ID:** 10933385
- **Project number:** 5R35GM148357-02
- **Recipient organization:** NEW YORK UNIVERSITY SCHOOL OF MEDICINE
- **Principal Investigator:** HYUNG D RYOO
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $423,750
- **Award type:** 5
- **Project period:** 2023-09-22 → 2028-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10933385

## Citation

> US National Institutes of Health, RePORTER application 10933385, Translational control of stress response signaling (5R35GM148357-02). Retrieved via AI Analytics 2026-05-24 from https://api.ai-analytics.org/grant/nih/10933385. Licensed CC0.

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