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Defining the Multi-Omics Landscape of Phospholamban-induced Cardiomyopathy for Precision Medicine

Award Number: R01HL181422
ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 06/01/2026
PERIOD OF PERFORMANCE END DATE: 02/28/2030

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Defining the Multi-Omics Landscape of Phospholamban-induced Cardiomyopathy for Precision Medicine - PROJECT SUMMARY/ABSTRACT Dilated cardiomyopathy (DCM) is a leading cause of heart failure, with approximately 40% of DCM cases linked to pathogenic genetic variants. Despite advances in genetic testing, there remains a major knowledge gap in how specific variants contribute to the multifaceted clinical manifestations of DCM. A notable example is a pathogenic variant in the phospholamban (PLN) gene resulting from deletion of arginine 14 (PLN-R14del). PLN induces DCM characterized by prominent ventricular arrhythmias and highly variable phenotypes, ranging from severe, early-onset disease to lifelong asymptomatic carriage. Such variability makes it challenging to establish genotype-phenotype relationships in PLN-R14del carriers, highlighting the urgent need for new technologies to bridge this gap. Advances in omics technologies are revolutionizing precision medicine. Among omics methods, top-down proteomics has emerged as a powerful technology for studying post-translational modification (PTMs), genetic variants, and splicing isoforms (collectively known as “proteoforms”). Top-down proteomics is ideally positioned for studying complex genetic diseases like PLN-R14del DCM, providing direct evidence of how genetic mutations affect proteoform compositions and linkage to function and phenotype, thereby bridging genotype-phenotype gap. Our preliminary data show that the PLN-R14del variant is associated with unique changes in cardiac proteoforms, including alterations in critical Ca2+-handling, contractile, and metabolic proteoforms, in both human patient tissue and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Hence, we hypothesize that dysregulation of Ca2+-handling, contractile, and metabolic proteoforms and the corresponding pathways contribute to variability in disease phenotypes and expressivity in PLN-R14del carriers. To test this hypothesis, we will employ a systems biology approach featuring novel multi- omics, incorporating proteomics, metabolomics and lipidomics, in combination with human clinical samples and patient-derived hiPSC-CM cellular models. Specifically, we will carry out multi-omics analysis of myocardial tissue from patients with PLN-R14del DCM, compared with genotype-negative DCM and nonfailing donor tissue as controls. The findings from the omics analyses will be further integrated with clinical data to develop patient- specific disease signatures in PLN-R14del carriers. We will also determine differences between symptomatic and asymptomatic PLN-R14del carriers through multi-omics analysis of patient-derived and isogenic control hiPSC-CMs and link them to changes in contractility/metabolism using functional assays. We will further connect the PLN-R14del variant mechanistically to proteoform alterations and their functional outcomes using gain- and loss-of-function approaches. Successful completion of the proposed study will provide new insights into the mechanisms underlying cardiac dysfunction in PLN-R14del, as well as bridge the genotype-phenotype knowledge gap in familial DCM to improve risk-stratification in variant carriers, advance our understanding of genetic diseases, and facilitate the development of targeted treatments towards precision medicine.


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 = $747,262 )
2026	2026	UNIVERSITY OF WISCONSIN SYSTEM	21 N PARK ST STE 6301	MADISON	WI	53715	DANE	USA	Cardiovascular Diseases Research	000	1	6/15/2026	NEW	$747,262
														Subtotal = $747,262

Grand Total All Awards = $747,262

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Defining the Multi-Omics Landscape of Phospholamban-induced Cardiomyopathy for Precision Medicine

Award Number: R01HL181422

ORGANIZATION: NATIONAL HEART, LUNG, & BLOOD INSTITUTE

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 06/01/2026

PERIOD OF PERFORMANCE END DATE: 02/28/2030

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