Nuclear Receptor Function in Stress Responses

描述(申请人提供)：环境挑战(如饥饿、损伤、炎症、寒冷、运动、缺氧、心理应激源)对应激反应的瞬时激活通过调节免疫系统、刺激心血管系统和动员能量来源发挥保护作用。然而，应激反应系统的慢性激活会导致“磨损”，并使机体易于残疾和疾病。糖皮质激素的异常产生或利用尤其与抑郁症、中心性肥胖症和心血管疾病有关。我们的长期目标是了解整合糖皮质激素受体(GR)和其他核受体活性的调控网络，并使其能够对应激做出特定和协调的转录反应。作为实现这一目标的第一步，我们将研究转录共激活因子PGC-1和孤儿核受体ERRpha在应激反应和GR介导的转录中的功能。这项拟议的工作将检验这样一种假设，即PGC-1和ERRpha是调节应激和糖皮质激素转录反应的关键传感器。在它们的传感器作用下，PGC-1和ERRpha可能向GR信号传递细胞类型、生理状态或应激源信息。为了验证我们的假设，我们将：i)确定不同应激源诱导PGC-1和ERRpha的能力；ii)剖析ERRpha在PGC-1介导的细胞代谢调节中的作用；iii)定义受ERRpha调控的内源性GR靶点，并阐明使ERRpha能够调节GR介导的转录的启动子背景；iv)使用转基因小鼠来检查整合GR-1、ERRα-和PGC-1传递的信号的特定应激反应。我们的研究将为GR反应提供特异性和多功能性的机制，以及PGC-1和ERRpha尚未确定的功能提供见解。了解控制压力反应的机制是制定应对其有害影响的战略的重要一步。

DESCRIPTION (provided by applicant): Transient activation of stress responses by environmental challenges, (e.g. starvation, injury, inflammation, cold, exercise, hypoxia, psychological stressors) play protective roles by regulating the immune system, stimulating the cardiovascular system, and mobilizing energy sources. Chronic activation of the stress response system can however lead to "wear and tear", and predispose the organism to disability and disease. Aberrant production or utilization of glucocorticoids in particular has been associated with depression, central adiposity, and cardiovascular disease. Our long term goal is to understand the regulatory networks that integrate the activity of the glucocorticoid receptor (GR) and other nuclear receptors, and enable specific and coordinated transcriptional responses to stress. As a first step towards this goal, we will study the functions of the transcriptional coactivator PGC-1 and the orphan nuclear receptor ERRalpha in stress responses and in GR - mediated transcription. The proposed work will test the hypothesis that PGC-1 and ERRalpha are key sensors that regulate the transcriptional response to stress and glucocorticoids. In their sensor role, PGC-1 and ERRalpha may convey cell-type, physiologic-state, or stressor information to GR signaling. To test our hypothesis, we will: i) determine the ability of distinct stressors to induce PGC-1 and ERRalpha; ii) dissect the role of ERRalpha in PGC-1 - mediated regulation of cellular metabolism; iii) define endogenous GR targets that are regulated by ERRalpha, and elucidate the promoter context that enables ERRalpha to regulate GR-mediated transcription; iv) use genetically-modified mice to examine specific stress responses that integrate GR-, ERRalpha-, and PGC-1 - transmitted signals. Our studies will provide insights into mechanisms that provide specificity and versatility to GR responses, and into yet uncharacterized functions of PGC-1 and ERRalpha. Understanding the mechanisms that control the response to stress is an important step in devising strategies to combat its harmful impacts.