Regulation and biology of the orphan receptor ERR

描述（由申请人提供）： 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PPARgamma Coactivator 1（PGC-1）是将信号转导至参与细胞能量产生的基因的优秀候选者。PGC-1 α显示出独特的组织特异性和发育表达谱，并可通过环境刺激诱导，如冷暴露，禁食和运动。通过其作为转录辅激活因子的功能，PGC-1 α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共激活许多转录因子，最显著的是核受体超家族的成员。PGC-1 α表达在病理状态下改变，如糖尿病和心脏肥大，PGC-1 α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α（ERRalpha），作为一种新的PGC-1 α的合作伙伴。该提议旨在验证以下假设：PGC-1 α是ERR α及其相关亚型ERR γ的真正共激活剂; ERR介导PGC-1 α对生理刺激的不同代谢调节作用。为了证明PGC-1a是ERR共激活因子，将使用细胞培养中的转录测定和体外结合研究来表征PGC-1alpha/ERR相互作用的功能和结构特征。ERR亚型在介导PGC-1 α下游代谢效应中的作用将通过表征功能丧失（ERRa缺失小鼠）和功能获得（细胞中ERR亚型的腺病毒过表达）模型中的代谢表型来确定。该项目的长期目标是确定PGC-1 α/ERR在控制肌肉和脂肪组织中与生理和病理过程相关的细胞代谢稳态反应中的作用。

DESCRIPTION (provided by applicant): 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, PPARgamma Coactivator 1 (PGC-1), is an excellent candidate for transducing signals to genes involved in cellular energy production. PGC-1alpha 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-1alpha regulates a wide array of cellular metabolic processes, including mitochondrial oxidative pathways in heart, skeletal muscle, and brown adipose; and gluconeogenesis in liver. PGC-1alpha coactivates a number of transcription factors, most notably members of the nuclear receptor superfamily. PGC-1alpha expression is altered in pathologic states, such as diabetes mellitus and cardiac hypertrophy, and PGC-1a polymorphisms have been linked to increased risk of diabetes mellitus in humans. Recently, we have identified the nuclear orphan receptor, estrogen-related receptor a (ERRalpha), as a novel PGC-1alpha partner. This proposal is designed to test the hypotheses that PGC-1alpha functions a bona fide coactivator for ERRalpha and its related isoform, ERRgamma; and that the ERRs mediate distinct metabolic regulatory effects of PGC-1alpha in response to physiologic stimuli. To demonstrate that PGC-1a is an ERR coactivator, functional and structural features of the PGC-1alpha/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-1alpha will be determined by characterizing the metabolic phenotypes in both loss-of-function (ERRa 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-1alpha/ERR in the control of a subset of cellular metabolic homeostatic responses relevant to physiologic and pathologic processes in muscle and adipose tissue.