Regulation and biology of the orphan receptor ERR

超出所提供的空间。适当调节ATP生成所涉及的细胞代谢过程对于正常组织发育和体内平衡是必要的。细胞ATP生成的能力受到发育、生理和环境因素的调节，需要从细胞表面到细胞核的转导事件。转录辅激活因子，过氧化物酶体增殖物激活因子/辅激活因子1（PGC-1），是一个很好的候选人转导信号的基因参与细胞能量的生产。PGC-lc_显示出独特的组织特异性和发育表达谱，并且可通过环境刺激（如冷暴露、禁食和运动）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、骨骼肌和棕色脂肪中的线粒体氧化途径;以及肝脏中的线粒体生成。PGC-1 α t共激活许多转录因子，最显著的是核受体超家族的成员。PGC-lo：在病理状态如糖尿病和心脏肥大中表达改变，并且PGC-Ic多态性与人患糖尿病的风险增加有关。最近，我们已经确定了核孤儿受体，雌激素相关受体ot（ERR（x），作为一种新的PGC-批次的合作伙伴。该提议旨在验证以下假设：PGC-lc_1是ERR α及其相关亚型ERRs的真正共激活剂;并且ERRs介导PGC-lc_1响应生理刺激的不同代谢调节作用。为了证明PGC-1c_是ERR共激活剂，将使用细胞培养中的转录测定和体外结合研究来表征PGC-1c_/ERR相互作用的功能和结构特征。ERR同种型在介导PGC-Ic_下游代谢效应中的作用将通过表征功能丧失（ERRc_ null小鼠）和功能获得（细胞中ERR同种型的腺病毒过表达）模型中的代谢表型来确定。该项目的长期目标是确定PGC-lcdERR在控制与肌肉和脂肪组织中的生理和病理过程相关的细胞代谢稳态应答的子集中的作用。性能现场=

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