The central theme of this PPG is to elucidate the molecular intersection of novel adrenergic receptor signaling pathways involved in the physiological and pathological growth of the heart. The ultimate goal is to identify novel molecules and pathways that have the potential to become therapeutic targets in the treatment of heart failure with a theme centered on signaling mechanisms of adrenergic receptors. The experimental organization is crafted such that the specific aims for each project address both basic molecular mechanisms of G-protein-coupled receptor signaling using in vitro and cell culture methods, and the translation of these fundamental concepts into relevant in vivo models of hypertrophy and heart failure. Since each project contains both basic and translational components, we are uniquely positioned in this PPG to take basic discoveries made at the bench and move them into clinically relevant in vivo models of heart failure. This well focused PPG will be led by project leaders who have had a long history of collaboration, as demonstrated by numerous co-authored publications and collaborative grants. The history of close collaboration between the project leaders has resulted in thematically integrated projects, ideally suited for a PPG. We propose 4 projects that each address a unique aspect of adrenergic signaling and will be directed by project leaders that are distinguished scientists in their field. The themes for each of the 4 projects are: Project 1 (Rockman) will study novel aspects of phosphoinositide 3-kinase (PI3K) in beta-adrenergic receptor (beta-AR) internalization; Project 2 (Koch) will study novel aspects of the beta-AR kinase and its regulation of myocardial beta-AR signaling; Project 3 (Stamler and Lefkowitz) will study a new paradigm for beta-AR signaling through regulation by nitric oxide; and Project 4 (Williams and Rosenberg) will study novel aspects of cardiac calcium signaling regulated by G-protein-coupled receptor (GPCR) stimulation. We propose two scientific cores that are integral to the success of the program by providing both small animal and large animal expertise where the novel concepts identified at the bench can be tested as potential therapeutic targets in large animal models of heart failure. We believe this highly synergistic program combines uniquely talented investigators with cutting edge molecular and in vivo animal model methodologies, which will lead to novel discoveries in adrenergic receptor signaling and potential new therapeutic avenues in heart failure.
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