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

描述(申请人提供)：心脏的泵功能是基于肌节蛋白的运动，并依赖于持续的ATP供应。ATP的磷酸键中所含的能量反过来由提供能量的底物的新陈代谢提供。能够很容易地利用葡萄糖和脂肪两种燃料来源，对于保护心脏功能至关重要。在血流动力学应激条件下，如对经主动脉缩窄(TAC)的反应，心脏通过代谢改变和三条主要信号通路的改变而做出反应，导致肥厚，代谢和肌瘤基因的表达改变。这种协调反应表明，在独立途径的效应器蛋白的上游，存在整合这些应激反应途径的因子。我已经确定SRC-2是这些通路中每一个的主要调节因子。SRC-2在小鼠心脏中的缺失导致代谢和肌瘤基因的基因表达重塑，以及对TAC的反应缺乏肥厚。此外，SRC-2的缺失导致TAC上能量缺乏的增加。我假设SRC-2是心脏基因表达程序的关键调节因子，其活性是心脏应激反应对血流动力学超负荷的协调的组成部分。我的项目建议研究代谢和时间特征以及SRC-2活性在心脏对主动脉收缩的反应中的作用。K99部分完成了对SRC-2在控制心脏功能中的作用的全面研究的初步数据，并专注于培育心脏特异的小鼠模型，该模型将允许SRC-2的可诱导缺失。这个模型将被用来研究心脏特异性SRC-2缺失的分子和生理后果。这些研究将过渡到R00部分，该部分使用这个模型来表征SRC-2活性的主要和次要目标，以及这些目标在心脏应激期间是如何协调控制的。心脏应激开始、代谢变化和其他压力超负荷诱导通路的信号之间的相互作用也将被研究。结合职业发展培训，包括指导、课程工作和演示机会，这些研究将扩展我在新陈代谢控制和心血管系统方面的分子培训，为我在分子心脏病学领域的独立职业生涯奠定坚实的基础。

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.