Cardiac Lineage-Specific Molecular Mechanisms of Heart Failure

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Project Summary The heart consists of a multitude of diverse cardiac cell types that form cardiac structures critical for maintaining heart function. These cell populations include not only cardiomyocytes, cardiac fibroblasts, epicardial cells, endothelial/endocardial cells and smooth muscle cells, but also more specialized cell types comprising the cardiac valves, cardiac conduction system, etc. Thus, regulated maintenance of these cell types is crucial for optimal heart performance, and disrupting the function of specific cell lineages can result in distinct heart diseases including heart failure (HF), which is a major leading cause of morbidity and mortality worldwide. However, what are the specific cell lineages affected during HF and how do gene regulatory networks (GRNs) control genetic programs that direct their pathologic outcomes are key biomedical questions that we seek to address in our parent R01HL156576 grant. Toward this end, this grant proposal has mainly focused on analyzing the cardiac chambers (i.e., ventricles and atria) but not cardiac valves, which can be defective and diseased in HF and in some cases can be the cause of HF. Thus, to expand our efforts and examine all cell-types participating in failing and non-failing human hearts in vivo including the cardiac valves, we propose to implement joint single cell/nuclear (sc/sn) RNA-seq and ATAC-seq technologies (i.e., single cell multi-omics) on not only the cardiac chambers as originally proposed in our parent grant but also the cardiac valves, particularly mitral valve, in response to the Notice of Special Interest (NOSI): Administrative Supplements to Encourage Research in Valvular Heart Disease (CAROL Act, NOT-HL-23-078). In addition to identifying distinct CV cell-types and their related transcriptional profiles and chromatin landscape, we further seek to elucidate the interactions between cell-type specific cis-regulatory elements (CREs), which mediate the GRNs that control how CREs direct gene expression of these cell types in the cardiac (mitral) valves of failing and non-failing hearts. Furthermore, because the structural form of the cardiac valve is critical for regulating its function, we propose to further investigate the spatial organization of identified cell types in the cardiac valves, particularly mitral valves, of human hearts with and without heart failure and cardiac valve defects/disease. Thus, the overall goal of this supplement to our original parent grant is to generate single-cell multi-omics and spatial imaging data of cardiac valves, particularly mitral valves, from a large, well-phenotyped cohort of patients with and without heart failure and mitral valve defects/disease. We will then create comprehensive maps of cell-type specific gene regulation including integrated genomic profiles and spatial localization of all cells and cis-regulatory programs in each cell type.