A Novel Role for IKKbeta in Epicardial Adipose Tissue Formation

The main research interest of my laboratory is to understand the molecular mechanisms of cardiometabolic disease. The Transformational Project Award will study a new cardiovascular research topic – mechanisms regulating epicardial adipose tissue (EAT) formation and its impact on cardiac remodeling. EAT volume has been positively associated with atrial fibrillation and increased cardiovascular disease risk in clinical studies, but the origin and factors regulating EAT formation remain elusive. The goal of this project is to investigate the novel functions of IKKbeta, a central coordinator of inflammation and immune responses, in the regulation of EAT formation and cardiac remodeling. A number of progenitor cells within epicardium can undergo an epithelia-to-mesenchymal transition (EMT) after myocardial infarction (MI) to form multipotent mesenchymal epicardium-derived cells (EPDCs) which are mesenchymal stem-like cells that can give rise to multiple cell lineages. The molecular mechanisms underlying EPDC fate determination are poorly understood, and the contribution of IKKbeta signaling to MI-induced EAT formation as well as cardiac remodeling has not been studied. In this application, I am proposing to investigate the functions of IKKbeta in the regulation of MI-induced EPDCs differentiating into EAT, and to elucidate the detailed mechanism through with IKKbeta regulates EPDC fate. The proposed studies will provide novel mechanistic links explaining how MI induces EAT formation, and will contribute to our understanding of EAT and CVD risk relationship. Furthermore, this project will lay the foundation for long-term projects examining the relationship among IKKâ signaling, inflammation, EAT formation and cardiac remodeling.