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

描述（由申请人提供）：心脏的泵功能基于肌节蛋白的运动，并依赖于ATP的持续供应。ATP的磷酸键中所含的能量反过来又由提供能量的底物的代谢提供。容易使用葡萄糖和脂肪燃料来源的能力对于保护心脏功能至关重要。在血液动力学应激的条件下，例如响应经主动脉缩窄（TAC），心脏通过代谢的改变和三个主要信号通路的变化做出反应，导致肥大以及代谢和肌节基因表达的改变。这种协调的反应表明，上游的效应蛋白的独立途径有整合这些应激反应途径的因素。我已经确定SRC-2是这些途径中每一个的主要调节因子。小鼠心脏中SRC-2的缺失导致代谢和肌节基因的基因表达重塑以及响应于TAC的肥大缺乏。此外，SRC-2的缺失导致TAC后能量缺乏增加。我假设SRC-2是心脏基因表达程序的关键调节因子，其活性是心脏对血流动力学过载的应激反应协调的组成部分。我的项目建议检查代谢和时间的特点和SRC-2活性在心脏对主动脉缩窄的反应中的作用。K99部分通过初步数据完成了对SRC-2在控制心脏功能中的作用的全面检查，并专注于培育允许SRC-2诱导缺失的心脏特异性小鼠模型。该模型将用于研究心脏特异性SRC-2丢失的分子和生理后果。这些研究将过渡到R 00部分，该部分使用该模型来表征SRC-2活性的主要和次要靶点，以及这些靶点在心脏应激期间如何协调控制。还将研究心脏应激发作、代谢变化和其他压力超负荷诱导途径的信号传导之间的相互作用。结合职业发展培训，包括指导，课程工作和演讲机会，这些研究将扩展我在代谢控制和心血管系统方面的分子培训，为分子心脏病学的独立职业生涯提供坚实的基础。

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.