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LMNA Mutations: Mechanics and ROS in Cardiomyopathy

Award Number: F31HL188942
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS
PERIOD OF PERFORMANCE START DATE: 03/01/2027
PERIOD OF PERFORMANCE END DATE: 02/29/2028

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LMNA Mutations: Mechanics and ROS in Cardiomyopathy - PROJECT SUMMARY/ABSTRACT Dilated cardiomyopathy (DCM) caused by mutations in the LMNA gene constitutes a distinct and highly aggressive clinical entity, characterized by disproportionately high risk of sudden cardiac death (SCD) and severe conduction disease that often precedes structural heart failure. Despite the malignant nature of LMNA-related DCM, current clinical management relies on non-specific heart failure therapies and implantable defibrillators, which fail to address underlying molecular pathology. A critical barrier to precision medicine is lack of mechanistic understanding regarding how LMNA variants located in different functional domains—specifically C-terminal Ig- like domain versus coiled-coil rod domain—drive distinct cellular pathologies. Furthermore, while mitochondrial dysfunction and elevated reactive oxygen species (ROS) are emerging as key features of the disease, the mechanistic link connecting primary nuclear envelope defects to downstream mitochondrial failure remains unresolved. This F31 proposal utilizes a patient-derived induced pluripotent stem cell- cardiomyocyte (hiPSC-CM) model to bridge knowledge gaps. The central hypothesis is that LMNA variants across distinct domains differentially disrupt nuclear mechanotransduction and oxidative stress regulation, converging on a pathogenic feedback loop involving the LINC complex protein SUN1. Preliminary data was generated using a high-throughput SupRep-DM (Suppression Replacement-Disease Modeling) screening platform to identify high-priority variants; proposed research will employ CRISPR/Cas9 gene- edited hiPSC-CMs to rigorously define disease mechanisms in a controlled, isogenic genomic background. Aim 1: Establish a functional fingerprint for Ig-like, rod domain, and N-terminal variants using these gene- edited lines. Utilizing high-throughput Kinetic Image Cytometry (KIC) and high-resolution confocal microscopy, the project will quantify variant-specific defects in cardiomyocyte contractility, nuclear morphology, and mitochondrial ROS production. This aim seeks to define how specific mutation locations correlate with severity of mechanical instability and oxidative stress. Aim 2: Dissect the molecular mechanisms linking nuclear defects to cellular failure. Integrated transcriptomic and proteomic analyses will be used to identify dysregulated signaling pathways unique to each variant class. Targeted experiments will rigorously test the hypothesis that Ig-like domain variants disrupt Lamin-SUN1 binding, leading to the pathogenic accumulation of SUN1 and subsequent SIRT1-mediated mitochondrial dysfunction. This aim investigates therapeutic potential of normalizing SUN1 levels via RNA interference to rescue disease phenotype. This research is supported by a comprehensive training plan at Mayo Clinic. The candidate will gain specialized expertise in stem cell engineering, multi-omics data integration, and translational pharmacogenomics. By elucidating the precise molecular drivers of LMNA cardiomyopathy and validating SUN1 as a therapeutic target, this project paves the way for the first disease-modifying therapies for this lethal condition.


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 = $53,114 )
2026	2026	MAYO CLINIC	200 1ST ST SW	ROCHESTER	MN	55905	OLMSTED	USA	Cardiovascular Diseases Research	000	1	9/4/2026	NEW	$53,114
														Subtotal = $53,114

Grand Total All Awards = $53,114

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LMNA Mutations: Mechanics and ROS in Cardiomyopathy

Award Number: F31HL188942

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

PERIOD OF PERFORMANCE START DATE: 03/01/2027

PERIOD OF PERFORMANCE END DATE: 02/29/2028

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