EXCEED THE SPACE PROVIDED. Appropriate regulation of cellular metabolic processes involved in ATP-generation is necessary for normal tissue development and homeostasis. The capacity for cellular ATP generation is regulated by developmental, physiological, and environmental cues requiring transducing events from the cell surface to the nucleus. The transcriptional coactivator, PPAR,/Coactivator 1 (PGC-1), is an excellent candidate for transducing signals to genes involved in cellular energy production. PGC-lc_ displays a unique tissue-specific and developmental expression profile and is inducible by environmental stimuli, such as cold exposure, fasting, and exercise. Through its function as a transcriptional coactivator, PGC-lo_ regulates a wide array of cellular metabolic processes, including mitochondrial oxidative pathways in heart, skeletal muscle, and brown adipose; and gluconeogenesis in liver. PGC-1 ot coactivates a number of transcription factors, most notably members of the nuclear receptor superfamily. PGC-lo: expression is altered in pathologic states, such as diabetes mellitus and cardiac hypertrophy, and PGC-lc_ polymorphisms have been linked to increased risk of diabetes mellitus in humans. Recently, we have identified the nuclear orphan receptor, estrogen-related receptor ot (ERR(x), as a novel PGC-lot partner. This proposal is designed to test the hypotheses that PGC-lc_ functions a bonafide coactivator for ERR(x and its related isoform, ERRs,; and that the ERRs mediate distinct metabolic regulatory effects of PGC-lc_ in response to physiologic stimuli. To demonstrate that PGC-lc_ is an ERR coactivator, functional and structural features of the PGC-lo_/ERR interaction will be characterized using transcriptional assays in cell culture and in vitro binding studies. The role of ERR isoforms in mediating downstream metabolic effects of PGC-lc_ will be determined by characterizing the metabolic phenotypes in both loss-of- function (ERRc_ null mice) and a gain-of-function (adenoviral overexpression of ERR isoforms in cells) models. The long-term goal of this project is to define the role of PGC-lcdERR in the control of a subset of cellular metabolic homeostatic responses relevant to physiologic and pathologic processes in muscle and adipose tissue. PERFORMANCE SITE ========================================Section End===========================================
