Regulation and biology of the orphan receptor ERR

超出所提供的空间。参与atp生成的细胞代谢过程的适当调节是正常组织发育和稳态所必需的。细胞生成ATP的能力受到发育、生理和环境因素的调节，这些因素需要从细胞表面传导到细胞核。转录共激活因子PPAR / coactivator 1 （PGC-1）是将信号转导到参与细胞能量产生的基因的极好候选者。PGC-lc_具有独特的组织特异性和发育性表达谱，可受冷暴露、禁食和运动等环境刺激诱导。通过其作为转录辅激活因子的功能，PGC-lo_调节广泛的细胞代谢过程，包括心脏、骨骼肌和棕色脂肪的线粒体氧化途径；肝脏中的糖异生。PGC-1可协同激活许多转录因子，其中最显著的是核受体超家族的成员。PGC-lc_在病理状态下表达改变，如糖尿病和心脏肥厚，PGC-lc_多态性与人类糖尿病风险增加有关。最近，我们已经确定了核孤儿受体，雌激素相关受体（ERR(x)），作为一个新的PGC-lot合作伙伴。本研究旨在验证以下假设：PGC-lc_是ERR(x)及其相关异构体ERRs的真正共激活因子；ERRs介导PGC-lc_在生理刺激下的不同代谢调节作用。为了证明PGC-lc_是ERR共激活因子，PGC-lo_/ERR相互作用的功能和结构特征将通过细胞培养和体外结合研究的转录分析来表征。ERR异构体在介导PGC-lc_下游代谢作用中的作用将通过表征功能缺失（ERRc_缺失小鼠）和功能获得（细胞中腺病毒过表达ERR异构体）模型的代谢表型来确定。该项目的长期目标是确定PGC-lcdERR在控制与肌肉和脂肪组织的生理和病理过程相关的细胞代谢稳态反应中的作用。网站性能 ======================================== 节结束 ===========================================

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===========================================