The steroid receptor coactivator SRC-2 coordinates and modulates the metabolic, s

Baylor College Of Medicine, Houston TX

Investigators

Linked publications & trials

Abstract

DESCRIPTION (provided by applicant): The pump function of the heart is based on the movement of sarcomeric proteins and relies on a constant supply of ATP. The energy contained in the phosphate bonds of ATP is, in turn, supplied by the metabolism of energy providing substrates. The ability to readily use both glucose and fat fuel sources is paramount to preserving cardiac function. Under conditions of hemodynamic stress, such as in response to transaortic constriction (TAC), the heart responds through alterations in metabolism and changes in three major signaling pathways, resulting in hypertrophy, and altered expression of metabolic and sarcomeric genes. This coordinated response suggests that upstream of the effector proteins for the independent pathways there are factors integrating these stress response pathways. I have identified SRC-2 as a major regulator of each of these pathways. Loss of SRC-2 in the mouse heart results in gene expression remodeling of both metabolic and sarcomeric genes as well as a lack of hypertrophy in response to TAC. Furthermore, loss of SRC-2 results in increased energetic deficiency upon TAC. I hypothesize that SRC-2 is a critical regulator of the cardiac gene expression program whose activity is an integral component of the coordination of the cardiac stress response to hemodynamic overload. My project proposes to examine the metabolic and temporal features and the role of SRC-2 activity in the cardiac response to aortic constriction. The K99 portion completes by preliminary data for a full examination of a role for SRC-2 in controlling cardiac function and is focused on breeding a cardiac-specific mouse model that will allow inducible deletion of SRC-2. This model will be used to investigate the molecular and physiological consequences of cardiac-specific loss of SRC-2. These studies will transition into the R00 portion, which uses this model to characterize the primary and secondary targets of SRC-2 activity, and how these targets are coordinately controlled during cardiac stress. Interplay between cardiac stress onset, metabolic changes, and signaling to other pressure overload induced pathways will also be investigated. Combined with career development training, including mentoring, course work, and presentation opportunities, these studies will extend my molecular training in metabolic control and the cardiovascular system, providing a strong basis for an independent career in molecular cardiology.