Tuesday, November 29, 2022
11/29/2022
PROJECT SUMMARY (OVERVIEW) The overarching goal of this Program Project Grant (PPG) is to better understand the mechanisms by which altered sodium (Na+) and calcium (Ca2+) signaling contribute to electromechanical dysfunction in heart failure (HF). Project 1 (Wu) will define the mechanism of Na+-Ca2+ dysregulation leading to arrhythmia in HF and explore the impact of genetic heterogeneity on this phenomenon in induced pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) derived from patients with mutations associated with dilated cardiomyopathy (DCM), which is a major cause of heart failure. Project 2 (Bers) will do parallel mechanistic studies in adult HF rabbit myocytes and intact hearts to understand how to break the vicious cycle Na+/Ca2+ dysregulation. Importantly, quantitative mechanistic results will inform and be validated by rabbit and human computational models. Project 3 (Mercola) will advance these investigations by taking a high-throughput approach to the electrophysiological phenotypes to elucidate the role of non-ion channel proteins in the cellular dysfunction and drug-induced arrhythmia, identifying novel therapeutic targets in this pathway, and generate an in silico model to predict arrhythmia susceptibility. An Administrative Core A (Wu) will support the three projects. Computational Modeling Core B (Grandi) will support all three projects by creating multi-scale computational models of iPSC- CMs and adult myocytes and tissues that incorporate patient-specific channel and drug effects. Together, these cross-disciplinary and synergistic studies will help lead to our goal of “Precision Medicine” for preventing HF and sudden cardiac death.
HHS’ Tracking Accountability in Government Grants System (TAGGS) website provides access to detailed descriptions of grants, loans, aggregated direct payments and other types of financial assistance awarded by the HHS Operating Divisions (OPDIVs) and the Office of the Secretary Staff Divisions (STAFFDIVs).
