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Understanding the roles of nuclear envelope proteins and DNA damage in cardiomyopathy

Award Number: K99HL171887
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP
PERIOD OF PERFORMANCE START DATE: 08/15/2024
PERIOD OF PERFORMANCE END DATE: 08/27/2025

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Understanding the roles of nuclear envelope proteins and DNA damage in cardiomyopathy - Project Summary Mutations in nuclear envelope proteins (NEPs) cause devastating genetic diseases, known as envelopathies, which primarily affect the heart and skeletal muscle. The LEM domain nuclear envelope protein 2 (LEMD2) is a ubiquitously expressed inner nuclear membrane protein. In vitro studies reported that LEMD2 interacts with DNA-binding proteins, implicating LEMD2 in genome regulation and chromatin organization processes. Importantly, a missense mutation in the LEMD2 coding sequence causes severe cardiomyopathy in humans. In a recent study, we reported that “humanized” mice carrying the Lemd2 c.T38>G human mutation as well as cardiac-specific Lemd2 KO (cKO) mice develop dilated cardiomyopathy (DCM) and die prematurely due to heart failure. Moreover, Lemd2- deficient cardiomyocytes (CMs) display high levels of DNA damage. Despite its association with cardiac phenotypes in both human and mice, the role of LEMD2 in the mammalian heart and the pathological mechanisms responsible for its association with cardiac disease are far from being understood. Based on my preliminary findings, I hypothesize that high levels of DNA damage in LEMD2-mutant CMs cause the development of cardiomyopathy. To test this hypothesis, I will first perform a comprehensive characterization of the DNA damage and DNA damage response (DDR) in both mice and human CMs carrying LEMD2 mutations. The second aim is focused on the mechanistic link between LEMD2 loss-of-function, DNA damage and cardiomyopathy. I will determine if LEMD2 interacts with the chromatin-binding protein BAF, and whether the LEMD2 c.T38>G mutation disrupts this interaction. I will also detect nuclear envelope ruptures, cytosolic DNA leakage, and the activation of the pro-inflammatory pathway cGAS in LEMD2-mutant CMs. The third aim will determine the therapeutic potential of LEMD2 gene therapy for envelopathies characterized by the presence of DNA damage. I will overexpress LEMD2 in CMs and mice carrying mutations in the lamin A gene and assess the extent of rescue at the structural and functional levels. By accomplishing the objectives of this proposal, we will reveal important mechanistic insights regarding LEMD2 functions and its associated cardiomyopathy. With this new knowledge, we hope to ultimately design new therapeutic strategies and preventive methods for genetic cardiomyopathies.


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 = -$106,127 )
2026	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	2	1/18/2026	NON-COMPETING CONTINUATION	-$106,127
														Subtotal = -$106,127

Issue Date FY: 2025 ( Subtotal = $100,480 )
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	001	2	8/28/2025	NON-COMPETING CONTINUATION	$0
2025	2025	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	2	8/11/2025	NON-COMPETING CONTINUATION	$100,480
														Subtotal = $100,480

Issue Date FY: 2024 ( Subtotal = $100,480 )
2024	2024	THE UNIVERSITY OF TEXAS SOUTHWESTERN MEDICAL CENTER	5323 HARRY HINES BLVD	DALLAS	TX	75390	DALLAS	USA	Cardiovascular Diseases Research	000	1	8/15/2024	NEW	$100,480
														Subtotal = $100,480

Grand Total All Awards = $94,833

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Understanding the roles of nuclear envelope proteins and DNA damage in cardiomyopathy

Award Number: K99HL171887

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: TRAINING/TRAINEESHIP

PERIOD OF PERFORMANCE START DATE: 08/15/2024

PERIOD OF PERFORMANCE END DATE: 08/27/2025

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