Investigating the role of the unfolded protein response in genetic dilated cardiomyopathy
Ended Project Grant Awarded Last action
- Award ID
- F32HL167558
- Recipient
-
The Leland Stanford Junior University UEI HJD6G4D6TJY5
- Awarding agency
-
National Heart Lung and Blood Institute
National Institutes of Health, Department of Health and Human Services
- Obligated
- $191,320
Award facts
- Assistance listing
- 93.837 Cardiovascular Diseases Research
- Completion date
- Place of performance
- Palo Alto, CA 94304, USA
Award details come from USAspending.gov.
Description
- Abstract
- 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.
Transactions
| Action | Obligated | Date |
|---|---|---|
| Amendment | $31,808 | |
| Amendment | $0 | |
| Amendment | $0 | |
| Amendment | $79,756 | |
| Original award | $79,756 |
Quick answers
Who received award F32HL167558?
F32HL167558 was awarded to The Leland Stanford Junior University by National Heart Lung and Blood Institute (National Institutes of Health) on September 30, 2024.
How much is award F32HL167558 worth?
$191,320 has been obligated on F32HL167558.
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