Regulation and biology of the orphan receptor ERR

超出提供的空间。对细胞代谢过程进行适当的调节对于正常的组织发育和动态平衡是必要的。细胞产生三磷酸腺苷的能力受发育、生理和环境信号的调节，这些信号需要将事件从细胞表面传递到细胞核。转录辅助激活因子PPAR/辅助激活因子1(PGC-1)是向细胞能量产生相关基因传递信号的一个很好的候选基因。PGC-LC_显示独特的组织特异性和发育表达谱，并可被环境刺激诱导，如冷暴露、禁食和运动。PGC-LO_1作为转录共激活因子，调节多种细胞代谢过程，包括心肌、骨骼肌和棕色脂肪中的线粒体氧化途径，以及肝脏中的糖异生。PGC-10T共激活了许多转录因子，尤其是核受体超家族的成员。PGC-LO：在糖尿病和心肌肥厚等病理状态下，PGC-Lc基因的表达会发生改变，PGC-Lc基因的多态性与人类患糖尿病的风险增加有关。最近，我们发现了核孤儿受体--雌激素相关受体ot(err(X))，它是一个新的PGC-LOT合作伙伴。本研究旨在验证以下假设：PGC-LC_1是ERR(X)及其相关异构体ERR(X)的真正共激活子；ERRS介导PGC-LC_2对生理刺激的不同代谢调节作用。为了证明PGC-Lc_1是ERR共激活剂，将利用细胞培养和体外结合研究中的转录分析来表征PGC-LO_/ERR相互作用的功能和结构特征。ERR亚型在介导PGC-1c下游代谢效应中的作用将通过鉴定功能丧失(ERRC_空小鼠)和功能获得(细胞中腺病毒过度表达ERR亚型)模型的代谢表型来确定。这个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一系列细胞代谢稳态反应中的作用。表演网站========================================Section End===========================================

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