Official websites use .gov

A .gov website belongs to an official government organization in the United States.

Secure .gov websites use HTTPS

A lock ( 🔒 ) or https:// means you've safely connected to the .gov website. Share sensitive information only on official, secure websites.

Need Help

Therapeutic insights into DELE1-mediated Integrated Stress Response in the heart

Award Number: R01HL178765
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 07/20/2026
PERIOD OF PERFORMANCE END DATE: 04/30/2030

Group Awards By:

View Award Description

Therapeutic insights into DELE1-mediated Integrated Stress Response in the heart - PROJECT SUMMARY The integrated stress response (ISR) is a pivotal cellular signaling cascade activated by various cellular stressors. Given that dysregulation of the ISR is strongly associated with the pathogenesis of a broad range of complex diseases, the ISR has emerged as an attractive therapeutic target for heart disease and non-cardiac disorders. The newly identified protein, DAP3 binding cell death enhancer 1 (DELE1), specifically mediates mitochondrial dysfunction-triggered ISR but is not responsible for ISR triggered by other stressors, thus providing opportunity to specifically modulate the ISR triggered by mitochondrial stress, and also allowing for the possibility of activating ISR through DELE1. Despite extensive efforts to develop strategies to activate or inhibit the ISR, achieving effective therapeutic outcomes remains a challenge, largely due to an incomplete understanding of their pathophysiological roles in the heart. In our preliminary studies, we titrated the extent of DELE1-mediated ISR in mitochondrial cardiomyopathy by either completely or heterozygously knocking out Dele1, and activating ISR through Dele1 overexpression in cardiomyocytes (CMs) at baseline. Our published studies have demonstrated that complete loss of DELE1 abolishes ISR activation and exacerbates cardiac phenotypes in mitochondrial cardiomyopathy, aligning with the concept that the ISR is protective. Surprisingly, our recent results revealed that, contrary to the protective role, ISR activation in embryonic CMs by overexpression of DELE1 leads to cardiomyopathy at baseline. The detrimental effects observed from either abolishing or enhancing the ISR suggest that maintaining optimal ISR levels is essential to favor protective effects while limiting adverse events. Remarkably, we found that Dele1 heterozygosity attenuates ISR signaling and ameliorates heart failure in mitochondrial cardiomyopathy, suggesting that reducing DELE1-mediated ISR could be a potential therapy for mitochondrial cardiomyopathy. A series of pharmacological interventions activating the ISR for treatment of various diseases are currently under pre-clinical investigation. Cardiac phenotypes caused by ISR activation in embryonic CMs cautions judicious use of ISR activators. To investigate the temporal effects, we activated the ISR in CMs at different stages. We found that ISR activation in pre- or early-adolescent CMs, but not in adult CMs, cause cardiac phenotypes at baseline, suggesting detrimental effects of ISR activation in CMs prior adult stages. Thus, our central hypothesis is that reduction of DELE1 expression is a potential treatment for mitochondrial cardiomyopathy, while activation of the ISR in the heart can cause adverse effects. Specific Aims are: 1) To investigate whether reducing DELE1 expression is a potential therapeutic approach for mitochondrial cardiomyopathy; and 2) To determine the potential cardiac side effects of activating the ISR by utilizing inducible CM-specific Dele1 overexpression (icOE) mice.


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2026 ( Subtotal = $779,166 )
2026	2026	UNIVERSITY OF CALIFORNIA, SAN DIEGO	9500 GILMAN DR	LA JOLLA	CA	92093	SAN DIEGO	USA	Cardiovascular Diseases Research	000	1	7/22/2026	NEW	$779,166
														Subtotal = $779,166

Grand Total All Awards = $779,166

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Therapeutic insights into DELE1-mediated Integrated Stress Response in the heart

Award Number: R01HL178765

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

PERIOD OF PERFORMANCE START DATE: 07/20/2026

PERIOD OF PERFORMANCE END DATE: 04/30/2030

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer