# Cellular Stress Response Mechanisms

> **NIH NIH R35** · BRIGHAM AND WOMEN'S HOSPITAL · 2021 · $614,328

## Abstract

Project Summary
The objective of this proposal is to determine how cells optimize survival in the face of adverse environmental
conditions. The proposed research is a continuation of a long-standing program designed to understand how
stress signaling pathways including phosphorylation of eIF2α, hypophosphorylation of 4EBP-1, and
angiogenin-induced tRNA cleavage re-program protein translation and induce the assembly of stress granules
(SGs) to modulate cell survival. Our central hypothesis is that these signaling pathways modulate the
expression of pro-growth and pro-survival proteins in ways that can be exploited for the treatment of cancer
and neurodegenerative disease. This is based upon our findings that ANG selectively cleaves tRNAs to
produce bioactive fragments (i.e., tiRNAs) that use multiple mechanisms to inhibit translation initiation and
induce SG assembly. We have also found that different stress stimuli produce compositionally distinct SGs
that can either promote or inhibit cell survival. The rationale for the proposed research is that, once we know
how these signaling pathways re-program protein translation to modulate cell survival, we will be able to exploit
these events to treat cancer and neurodegenerative disease. We will test our central hypothesis by addressing
key knowledge gaps that are holding back progress in the field. These include: 1) an understanding of the role
played by RNA in the nucleation of SG assembly, 2) an understanding of the composition and function of SGs
that either promote or inhibit cell survival, 3) an understanding of the mechanism by which the SG nucleating
proteins G3BP1/2 promote SG assembly, 4) elucidation of the composition of tiRNA inhibitory complexes and
the identify of their target transcripts, 5) an understanding of how tiRNAs selectively modulate the translation of
mRNAs bearing 5'-terminal oligopyrimidine motifs, 6) an understanding of how G-quadruplex structures
modulate tiRNA function, and 7) elucidation of the different mechanisms by which individual tiRNAs inhibit
translation initiation. The contribution of the proposed research will be to determine how tiRNAs and SGs
modulate the survival of cells involved in the pathogenesis of cancer and neurodegenerative disease. This
contribution is significant because it provides a molecular basis for the development of pharmacologic
strategies to prevent stress-mediated tumor growth or motor neuron death. The proposed research is
innovative because it focuses on the downstream effectors of these stress response programs and attempts to
identify molecular targets that can be developed into novel therapeutics.

## Key facts

- **NIH application ID:** 10187585
- **Project number:** 5R35GM126901-04
- **Recipient organization:** BRIGHAM AND WOMEN'S HOSPITAL
- **Principal Investigator:** PAUL J. ANDERSON
- **Activity code:** R35 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $614,328
- **Award type:** 5
- **Project period:** 2018-07-13 → 2023-06-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10187585

## Citation

> US National Institutes of Health, RePORTER application 10187585, Cellular Stress Response Mechanisms (5R35GM126901-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10187585. Licensed CC0.

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