SC1 PROJECT SUMMARY Atrial fibrillation is the most common cardiac arrhythmia. The lifetime risk of atrial fibrillation increases with advancing age and other risk factors that include obesity, smoking, hypertension, and diabetes mellitus. Atrial fibrillation is often a progressive condition, frequently beginning with brief episodes that progress to longer episodes that do not terminate without either drug- or electrical shock induced cardioversion. The cost and health burden of atrial fibrillation are expected to rise as the American population ages and the obesity rates increase, thus highlighting the need for interventions and therapies that can slow the progression and reduce the burden of atrial fibrillation. The overall goal of the Atrial Fibrillation Post-GWAS: Mechanisms to Treatment PPG application is to translate AF genomic discoveries back to the bedside, focusing on genes to mechanisms, genes to drugs, and interactions of genes with metabolism and environment. Our central hypothesis is that increasing our knowledge about molecular mechanisms involved in genetic, metabolic and structural changes in the atria will allow us to pinpoint possible targets for safer and more effective therapeutic strategies. The Engineered Heart Tissue and Atrial Phenotyping Scientific Core 1 (SC1) will provide support for all Projects in this PPG application via two aims. Aim 1 will maintain and propagate inducible pluripotent stem cells (iPSCs), differentiate iPSCs to atrial- or ventricular-like cardiomyocytes (a-iCM, v-iCM), from these create engineered heart tissues, and maintain atrial fibroblasts. Aim 2 will coordinate the contractile, metabolic, and structural phenotyping of iCMs, EHTs, and mouse LA. SC1 provides unique access to human a-iCMs, as well as a-EHTs that will enable all investigators on this PPG to achieve their scientific goals in a coordinated and efficient manner. While we focus on a-iCMs and a-EHTs for most of the studies proposed in the Program, we also support studies using v-iCMs and v-EHTs that will help differentiate atrial vs. ventricular effects. Our experience with generating and maintaining human iCMs and EHTs provides an opportunity for Projects within our PPG to use this leading-edge technology to test innovative hypotheses. Importantly, the use of SC1 expertise for the phenotyping of these experimental models, including evaluation of contractile function, mitochondrial respiration, mitochondrial content, subcellular structure, and isolation of RNA ensures uniform methodology across multiple models, through all projects, and makes these techniques available to individual laboratories that were otherwise not feasible. SC1 eliminates duplication of effort and optimizes the use of personnel, equipment, and supplies. The unique expertise provided by SC1 will support the goal of this PPG to translate AF genomic discoveries back to the bedside.