Senescent Cell States in Single Ventricle Disease with Heart Failure

Project Summary Congenital heart disease (CHD) is the most common birth defect and a leading cause of infant fatality in the United States. With improvements in techniques for medical intervention, more and more newborns with CHD live to adulthood. Severe CHDs often lead to heart failure (HF), which is a leading cause of death in children and adults with CHDs. High mortality and the cost of required treatment for CHD patients pose a tremendous burden to public health. Therefore, there’s an urgent need to develop novel and more efficient CHD therapies. Single Ventricle Disease (CVD) is a severe form of congenital heart disease in which neonates are born with a missing or underdeveloped left ventricle. Current treatment procedures are extremely invasive and introduce new risks of progressive HF. In addition to causes related to suboptimal surgeries, the reasons for CVD patients to develop HF remain unknown and difficult to predict. Genetic, epigenetic, and environmental factors have all been implicated as causative mechanisms underlying maladaptive features in the myocardium. This R01 application will investigate CVD in human and mouse cardiac fibroblasts (FBs). The objectives of this application are to gain insights into CVD with the long-term goal of generating treatments that promote productive heart repair in failing CVD hearts. The central hypothesis is that functional studies based on our published human profiling studies will develop datasets that can be used to predict HF patient clinical outcomes and uncover new therapeutic CVD targets. The specific aims are 1) To investigate FB intrinsic molecular mechanisms that promote senescence in CVD-HF patients, 2) To investigate the molecular mechanisms that lead to metabolic remodeling in CVD FBs, and 3) To determine if pathologic outgoing signaling from CVD FBs to CMs have deleterious functional effects on CVD CMs. The project is conceptually and technically innovative. Concepts to be tested include new ideas in cardiac biology and cutting-edge single-cell genomics technologies to address hypotheses. The significance is high because there are no treatments for heart failure, and devising ways to improve patient outcomes is highly significant.