PROJECT SUMMARY/ABSTRACT Cardiac hypertrophy is a leading risk factor for heart failure. This remodeling, which occurs with various pathological insults including chronic hypertension, was long thought to be irreversible. However, clinical evidence suggests that partial reverse remodeling (regression) is possible in a small subset of patients with existing therapies and is associated with improved outcomes. The molecular mechanisms underlying regression remain poorly understood. Cardiac hypertrophy can also occur in healthy settings (e.g., pregnancy and exercise), although here it is rapidly reversible with removal of the stimulus. In my preliminary studies using animal models of physiological hypertrophy (post-prandial Burmese python, exercised and pregnant mice), I identified the transcription factor Forkhead box protein O1 (FOXO1) is inhibited during hypertrophy development and then upregulated with regression, leading to increased expression of autophagy genes. This finding led to the hypothesis that FOXO1-dependent autophagy might underly regression. The potential role of FOXO1 as a putative regulator of regression was corroborated using a small molecular inhibitor in an in vitro hypertrophy model. These findings suggest that modulating FOXO1 or its downstream gene targets may represent a new therapeutic avenue for heart failure. The goal of this research plan is to investigate the involvement of FOXO1 and autophagy in the regression of cardiac hypertrophy and to characterize the potential of targeting these factors for treating heart failure and reversing pathological remodeling. Specifically, I will use adenovirus-mediated gene therapy to deliver FOXO1 or downstream autophagy genes to cardiomyocytes cultured with factors that promote physiological or pathological. I will further explore the therapeutic potential of targeting this pathway in vivo, using adeno-associated virus gene therapy in a mouse heart failure model. My long-term goals are to identify how protein quality control mechanisms regulate cardiomyocyte size, function, and longevity, and how they are impacted in disease settings. This fellowship will help me develop expertise with designing and amplifying adenoviruses and adeno-associated viruses for the modulation of lead therapeutic targets/pathways in cell and animal models of hypertrophy. Moreover, the exposure to multiple in vitro and in vivo cardiac models will help prepare me for a career as an independent investigator of the biology underlying cardiac remodeling.