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.
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