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Normal function of the human heart relies on highly heterogeneous cell populations with specialized functions. In response to systemic stress and/or injury, reparative processes such as fibrosis occur contributing to adverse remodeling and promoting mechanical dysfunction, arrhythmias and heart failure. To obtain insights into trigger-response patterns in HFpEF, we will apply single-nucleus RNA-sequencing (snRNA-seq) to study the composition of cardiac cell populations in biopsies of HFpEF patients and murine models of diastolic dysfunction. We will characterize cardiac cell states and types, their expression networks and cellular circuits, and locate these in space. By comparing changes between non-failing hearts and HFpEF we will discern fundamental causes of maladaptive cardiac remodeling, characterize heterogeneous cellular responses and infer new therapeutic strategies.
Graphical Abstract: We will apply single cell technologies to define the cellular and molecular definition of disease associated changes between healthy and diseased hearts. In addition, with our spatial analysis we aim to define the regional architecture of cardiac cell types and states in HFpEF hearts. Our comparative analyses of cardiac cell populations will be accomplished by gene expression measurements and analysis of chromatin organization between clinical and preclinical HFpEF phenogroups.
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