This proposal entails a five-year training program focused on preparing the applicant for an independent career in academic cardiovascular medicine. This project aims to impart the skills and knowledge required for the applicant to achieve his long-term goal of bringing genomic insights into cardiovascular disease. The immediate training objectives of the applicant are to learn more sequencing techniques, to analyze datasets with more sophisticated network models, and to acquire further bench experience to validate in silico findings. Other objectives include developing administrative skill required to function autonomously and composing a body of work that will enable funding as an independent investigator. Under the guidance of his long-term mentor Michael Snyder and his carefully selected advisory committee of senior investigators, the applicant will have the resources and support to achieve these goals and transition to independence. Project Description Heart failure affects nearly six million Americans. Dilated cardiomyopathy (DCM) represents the largest class among those with systolic heart failure. Genetics is thought to play a role in only a minority of cases; yet, whatever the cause, including genetic, the enlarged left ventricles and thin, poorly contracting myocardial walls characteristic of the hearts of all these patients represent the outcome of a final common pathway. This structural remodeling is reflected on the molecular level by changes in the transcription of genes. Already, previous work in a murine system has shown the involvement of molecules affecting chromatin accessibility leading to the ectopic expression of fetal genes in dilated cardiomyopathy tissue. However, a global, systematic study of multiple layers of the epigenome and transcription factors has yet to be performed on human DCM tissues. Even before that, though, the rules regarding the governance of transcription by regulatory elements is only beginning to be understood. This proposal seeks to model elements of the regulome in model cell lines and normal tissues before trying to understand their alterations in diseased states. The ultimate goal is to apply integrativ analysis involving global, regulatory element data to gain new insights in the disease process of DCM and thereby uncover potential new avenues for therapeutics.
Heart failure is a debilitating and costly disease affecting nearly six million Americans. Dilated cardiomyopathy represents the most common form of heart failure. Even though dilated cardiomyopathy can be caused by many different reasons, in the end, the diseased hearts of these patients have similarities in size and shape. These changes are sure to be reflected on the molecular level by changes in how genes are read. This project seeks to find out the dysregulation occurring in how genes are read in dilated cardiomyopathy as potential new avenues for therapy.