DESCRIPTION (provided by applicant): During the preceding decade numerous interventional maneuvers that induce or inhibit remodeling, promote or prevent cell death, and damage or repair the heart have been described. Although successfully resolved in experimental models by managing signal transduction, implementing strategies to treat heart failure in a clinical setting requires more than creating a litany of molecular candidates. Successful treatment on a molecular level will depend, in large part, upon an integrated perspective of cellular survival under stress. Combinatorial modeling of cardiac survival signaling reveals many paths with a shared destination: protection of mitochondrial integrity. However, significant controversies persist regarding mechanisms of mitochondrial protection, with the interrelationships of molecules that mediate mitochondrial protection remaining largely unexplored. This Program Project addresses limitations in current understanding of myocardial cellular survival with opportunities for profound advances in conceptual and mechanistic approaches for mitigation of cardiomyopathic diseases characterized by cell death including ischemia, infarction, decompensation, and aging. While seemingly diverse, these conditions share loss of mitochondrial function and cell death as unifying characteristics that are inextricably linked. As such, our investigative team focuses upon a central goal: determining mechanisms that preserve mitochondrial integrity to enhance cellular survival and ultimately maintain cardiac function. Synergistic Program Components facilitate a multifaceted approach using novel methodologies to assess survival signaling and the impact of manipulating protective pathways upon mitochondria. Coordinated programmatic research will discover new regulatory mechanisms of mitochondrial function, cellular survival, and integration of heretofore disparate or unrecognized molecular elements into an essential unified perspective. Combined organ, cellular, and molecular approaches are essential for comprehensive and unequivocal validation of mechanisms leading to protection of mitochondria, and our emerging paradigm integrating cellular signaling, survival, and mitochondrial function reveals a web of co-dependent factors. Collectively, the factors, relationships, and consequences revealed by this Program Project will provide critical contextual knowledge for designing translational approaches amenable to rapid implementation of clinical treatment for heart disease.