# Investigating the role of the Unfolded Protein Response in Genetic Dilated Cardiomyopathy

> **NIH NIH F32** · STANFORD UNIVERSITY · 2024 · $79,756

## Abstract

Project Summary
Dilated Cardiomyopathy (DCM) is the leading cause of heart failure. Characterized by left ventricular dilation
and impaired contractility, DCM results in pump failure and arrhythmogenesis leading directly to heart failure
and sudden cardiac death. There are more than 50 genes implicated in DCM development that each produce a
common DCM pathology. Induced pluripotent stem cell derived cardiomyocytes (iPSC-CMs) carrying DCM
mutations display phenotypic aspects of genetic DCM, providing a powerful in vitro tool to study the cellular
and molecular mechanisms of the disease. Our previous work utilized a specific patient-derived DCM mutation
in iPSC-CMs and found that these cells, with a known phenotype of protein aggregation, exhibited increased
Endoplasmic Reticulum (ER) stress which resulted in an activation of the Unfolded Protein Response (UPR), a
compensatory and adaptive reaction to cell stress and aberrant protein folding. Further activating the UPR
pharmacologically reduced ER stress in these cells and rescued cardiomyocyte contractility, indicating a direct
link between the ER stress identified in this cell line and the impaired cardiac function seen in DCM. Our
preliminary findings identified that Activating Transcription Factor 4 (ATF4), a stress response transcription
factor, is a key mediator of the UPR upregulation that relieves the cardiomyocyte of ER stress. Endogenous
ATF4 expression is upregulated during UPR activation, however its efficacy as a transcription factor remains
inhibited in DCM. We have found that pharmacological bolstering of the UPR response increases ATF4
transcription factor activity and rescues cardiac contractility. The proposed research plan will investigate the
UPR across several DCM gene mutations to identify how impaired proteostasis results in cardiac dysfunction,
uncovering a novel phenotype in DCM which we believe will be broadly applicable to other cardiac diseases.
Further, we will investigate the mechanism of ATF4 rescue of ER stress induced contractility deficits in iPSC-
CMs and in mouse models of genetic DCM to reveal an new mechanism and therapeutic target for DCM.

## Key facts

- **NIH application ID:** 10998462
- **Project number:** 1F32HL167558-01A1
- **Recipient organization:** STANFORD UNIVERSITY
- **Principal Investigator:** Rachel Baum
- **Activity code:** F32 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $79,756
- **Award type:** 1
- **Project period:** 2024-09-30 → 2026-01-29

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10998462

## Citation

> US National Institutes of Health, RePORTER application 10998462, Investigating the role of the Unfolded Protein Response in Genetic Dilated Cardiomyopathy (1F32HL167558-01A1). Retrieved via MORVS 2026-10-25 from https://api.morvs.ai/grant/nih/10998462. Licensed CC0.

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