# Cell survival after ER stress

> **NIH NIH R21** · UNIVERSITY OF MICHIGAN AT ANN ARBOR · 2020 · $187,787

## Abstract

Project Summary:
The endoplasmic reticulum (ER) hosts such critical events as protein folding, lipid synthesis, and maintenance
of calcium homeostasis. ER stress occurs when increased demand for these activities is elicited by diverse
environmental challenges, metabolic fluctuations, or pathological conditions. When the capacity to meet
prolonged or severe demand is exceeded, cell death is often the result. Much of the existing literature has
focused on apoptotic mechanisms occurring at mitochondria. Many therapeutic strategies in protein misfolding
diseases are directed towards correcting protein misfolding or targeting apoptotic mechanisms. Even as these
approaches are important, we have discovered a new pathway in yeast that allows adaptation to ER stress.
The main hypothesis in this proposal is that mitochondrial biogenesis is an adaptive response to ER stress by
protecting cells against accumulation of reactive oxygen species (ROS) and cell death. Our hypothesis is
supported by preliminary results showing that increased mitochondrial mass induced by a low dose of ER
stressor results in increased resistance to a subsequent higher dose. In Specific Aim 1 of the proposal we will
determine the mechanism by which ER stress induces mitochondrial biogenesis. We have evidence that
adaptive response requires the retrograde signaling pathway that communicates mitochondrial needs to the
nucleus. We will determine whether mitochondrial-ER contact sites are required for communicating ER stress
to mitochondria. In addition, new genetic screens are proposed to identify new components required for
mitochondrial response to ER stress. In Specific Aim 2, we will determine whether adaptation to ER stress
occurs similarly in mammalian cells. We propose studies in thyroid (PCCL3) and pancreatic ß (INS-1) cell
lines as these secretory cells have exquisite sensitivity to ER stress. Of great biological and medical
significance, our aims should lead to discovery of new therapeutic targets for impaired ER stress response in
numerous diseases.

## Key facts

- **NIH application ID:** 9851773
- **Project number:** 5R21AG058862-02
- **Recipient organization:** UNIVERSITY OF MICHIGAN AT ANN ARBOR
- **Principal Investigator:** AMY Y CHANG
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $187,787
- **Award type:** 5
- **Project period:** 2019-02-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9851773

## Citation

> US National Institutes of Health, RePORTER application 9851773, Cell survival after ER stress (5R21AG058862-02). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/9851773. Licensed CC0.

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