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

类固醇受体共激活剂 SRC-2 协调和调节代谢，

• 批准号: 8704231
• 负责人: Erin L Reineke
• 金额: $ 12.45万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-19 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704231
• 关键词: Ablation; Affect; Breeding; Cardiac; Cardiac Myocytes; Cardiology; Cardiovascular system; Data; Energy Metabolism; Fatty acid glycerol esters; Gene Expression; Gene Targeting; Generations; Genes; Glucose; Heart; Heart failure; Hypertrophy; Hypoxia; Knock-out; Mentors; Metabolic; Metabolic Control; Metabolism; Modeling; Molecular; Molecular Profiling; Movement; Mus; Nutrient; Pathway interactions; Phenotype; Physiological; Proteins; Pump; Regulation; Relative (related person); Role; Signal Pathway; Signal Transduction; Source; Steroid Receptors; Stress; System; Time; Tissues; Training; Treatment Failure; Work; base; biological adaptation to stress; career; career development; constriction; gene function; heart function; heart metabolism; hemodynamics; inorganic phosphate; insight; mouse model; novel; pressure; programs; response; sensor; stressor

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.

描述（由申请人提供）：心脏的泵功能基于肌合成蛋白的运动，并依赖于ATP的持续供应。ATP的磷酸键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保持心脏功能至关重要。在血流动力学应激条件下，如在对经主动脉收缩（TAC）的反应中，心脏通过代谢的改变和三种主要信号通路的改变做出反应，导致肥厚，并改变代谢和肌肉基因的表达。这种协同反应表明，在独立途径的效应蛋白上游存在整合这些应激反应途径的因素。我已经确定SRC-2是这些途径的主要调节器。小鼠心脏中SRC-2的缺失导致代谢和肌肉合成基因的基因表达重塑，以及TAC反应中肥厚的缺失。此外，SRC-2的损失导致TAC时能量不足增加。我假设SRC-2是心脏基因表达程序的关键调节因子，其活性是血流动力学过载时心脏应激反应协调的重要组成部分。我的项目建议研究代谢和时间特征以及SRC-2活性在主动脉收缩心脏反应中的作用。K99部分完成了对SRC-2在控制心功能中的作用的全面检查的初步数据，并专注于培育一种心脏特异性小鼠模型，该模型将允许诱导删除SRC-2。该模型将用于研究心脏特异性SRC-2缺失的分子和生理后果。这些研究将过渡到R00部分，使用该模型表征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。心脏应激发作、代谢变化和其他压力过载诱导途径的信号传导之间的相互作用也将被研究。结合职业发展培训，包括指导、课程作业和演讲机会，这些研究将扩展我在代谢控制和心血管系统方面的分子训练，为我在分子心脏病学方面的独立职业生涯提供坚实的基础。