In response to a diverse range of cardiac stress conditions, cardiomyocytes coordinate a complex network of signaling pathways designed to maintain appropriate cardiac function. Some of these signaling pathways result in changes in the turnover rate of cardiomyocyte structural proteins and energy metabolism, both of which are crucial adaptations that aid in cardiomyocyte survival. It is now well known that the ubiquitin proteasome system (UPS) plays an integral role in these adaptations to stress. Likewise, nuclear hormone receptors, with their ability to rapidly affect translational responses when triggered, are also crucial for mediating the metabolic and hemodynamic changes that are necessary in order to maintain optimal cardiac function during cardiac stress conditions.
The aims of this grant are intended as a logical extension of our initial project designed to elucidate the role that cardiac-specific ubiquitin ligases play in regulating adaptive responses in the setting of cardiomyocyte stress.
The specific aims of this proposal are to: (1) Investigate the role of the MuRF family of proteins in nuclear hormone receptor pathway activation and activity; (2) Delineate how prolyl hydroxylase domain proteins regulate MuRFs 1-3 function; and (3) Assess the role of MuRF proteins in regulating the adaptive response to beta-adrenergic receptor-mediated stress. To accomplish these aims we have formulated a novel and highly integrated approach using both in vitro and in vivo assays. The scope of this proposal is intended to address relevant biological and physiological questions using sate of the art molecular biology techniques. In addition to providing a new basis to appreciate the role of targeted protein turnover as a key regulatory mechanism in cardiomyocyte biology, these studies will help us to predict whether these proteins represent new potential targets for intervention in diseases associated with maladaptive changes in cardiac physiology.
Being able to adapt to both physiological and pathophysiological stressors is essential for proper cardiac health. Cardiomyocytes.adapt by altering their metabolism and size, processes that require the synthesis of new proteins and the degradation of old ones. Our overall goal is to understand how protein turnover in cardiomyocytes is linked to their adaptive responses to stress and how this impacts cardiac health.
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