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

Mapping the cell specific DNA damage-induced molecular and bioelectrical responses in the 3D cardiac unit

Award Number: R01HL161106
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 12/15/2021
PERIOD OF PERFORMANCE END DATE: 11/30/2026

Group Awards By:

View Award Description

Mapping the cell specific DNA damage-induced molecular and bioelectrical responses in the 3D cardiac unit - PROJECT SUMMARY This project will test the hypothesis that DNA damage in cardiomyocytes activates p53 leading to mitochondrial alterations and secretion of paracrine factors that drive heart failure. The premise for this has been established from our preliminary data and from the work of others. First, DNA damage and activated DNA damage response (DDR) have been observed in cardiovascular disease (CVD) in humans. Second, studies also show evidence that multiple cell types in the cardiac unit, including cardiomyocytes (CM) and cardiac fibroblasts (CF) display markers of DNA damage and cellular senescence in several disease pathologies. Third, we have recently identified that nuclear DNA damage drives dilated cardiomyopathy. Specifically, cardiomyocyte-depletion of the DNA repair endonuclease, ERCC1-XPF in mice, upregulates the DNA damage response gene, p53, and leads to irregular mitochondrial cristae, accumulation of lipids and increased oxidative stress. Additionally, there is an increase in several cardiac failure and senescence associated markers. However, the exact molecular underpinnings and cell-specificity of these DNA damage-induced changes is poorly understood. One barrier to addressing this question in vivo has been lack of appropriate tools, where DNA damage can be introduced in only one cell type (e.g., CM) and its effect on CF and cardiac function can be investigated. Additionally, 2D cell culture and co-culture systems fall short, as they cannot reproduce tissue dynamics present in a cardiac unit. Herein, we have developed several tools enable the study of cell-cell communication of 3D multicellular system. Specific Aim 1 will map the molecular, functional, and architectural changes upon loss of ERCC1 in CM. In this aim, we will test the mechanistic role of p53 and reactive oxygen species on a number of cellular and mitochondrial parameters, as well as cardiomyocyte electrophysiology. Specific Aim 2 will test whether stochastic, spontaneous DNA damage in the CM or CF drives cardiac electromechanical dysfunction in a cell- autonomous or cell non-autonomous manner through a paracrine effect on neighboring cells. Here, we will analyze the pathological secretome upon genotoxic stress, as well as test the role of eliminating senescent cells on cardiac health. This work is technically innovative as it uses a number of unique tools including concomitant optical and bioelectrical measurements in 3D cardiac organoids. These contributions will be significant because DNA damage is unavoidable and intimately linked to cardiac health and disease. Our team is uniquely qualified to perform this work, with expertise in DNA damage/ repair, cellular senescence, nanofabrication, human iPSC- derived cardiac tissue engineering, and data science. This analysis, we believe, will increase our fundamental understanding of the connection between DNA damage and heart disease and potentially pave the way for new treatment strategies.


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 = $604,982 )
2026	2026	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	000	5	3/6/2026	NON-COMPETING CONTINUATION	$586,463
2026	2026	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	001	5	4/21/2026	NON-COMPETING CONTINUATION	$18,519
														Subtotal = $604,982

Issue Date FY: 2025 ( Subtotal = $625,815 )
2025	2025	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	001	4	8/15/2025	NON-COMPETING CONTINUATION	$62,581
2025	2025	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	000	4	11/12/2024	NON-COMPETING CONTINUATION	$563,234
														Subtotal = $625,815

Issue Date FY: 2024 ( Subtotal = $594,434 )
2024	2024	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	001	3	6/26/2024	NON-COMPETING CONTINUATION	$48,524
2024	2024	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	000	3	11/30/2023	NON-COMPETING CONTINUATION	$545,910
														Subtotal = $594,434

Issue Date FY: 2023 ( Subtotal = $623,154 )
2023	2023	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	001	2	3/6/2023	NON-COMPETING CONTINUATION	$62,315
2023	2023	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	000	2	12/8/2022	NON-COMPETING CONTINUATION	$560,839
														Subtotal = $623,154

Issue Date FY: 2022 ( Subtotal = $619,860 )
2022	2022	CARNEGIE MELLON UNIVERSITY	5000 FORBES AVE	PITTSBURGH	PA	15213	ALLEGHENY	USA	Cardiovascular Diseases Research	000	1	12/3/2021	NEW	$619,860
														Subtotal = $619,860

Grand Total All Awards = $3,068,245

Top

All Categories

About

Search

Reports

Data Submission

Award Information

Mapping the cell specific DNA damage-induced molecular and bioelectrical responses in the 3D cardiac unit

Award Number: R01HL161106

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 12/15/2021

PERIOD OF PERFORMANCE END DATE: 11/30/2026

Federal Websites

Department of Health & Human Services

HHS Operating Divisions

HHS Staff Divisions

Download A Document Viewer