Regulation and biology of the orphan receptor ERR

孤儿受体 ERR 的调控和生物学

• 批准号: 6706402
• 负责人: JANICE M HUSS
• 金额: $ 8.86万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-02-15 至 2005-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6706402
• 关键词: Regulation; biology; orphan; receptor; ERR

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.

描述（由申请人提供）： 适当调节参与 ATP 生成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。转录共激活因子 PPARgamma 共激活因子 1 (PGC-1) 是将信号转导至参与细胞能量产生的基因的绝佳候选者。 PGC-1alpha 显示出独特的组织特异性和发育表达谱，并且可由环境刺激（例如寒冷暴露、禁食和运动）诱导。通过其作为转录共激活剂的功能，PGC-1α 调节多种细胞代谢过程，包括心脏、骨骼肌和棕色脂肪中的线粒体氧化途径；和肝脏中的糖异生作用。 PGC-1α 共同激活许多转录因子，尤其是核受体超家族的成员。 PGC-1α 表达在病理状态下发生改变，例如糖尿病和心脏肥大，并且 PGC-1a 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 a (ERRalpha)，作为一种新的 PGC-1alpha 伴侣。该提案旨在测试以下假设：PGC-1alpha 是 ERRalpha 及其相关亚型 ERRgamma 的真正共激活剂； ERR 介导 PGC-1α 对生理刺激的独特代谢调节作用。为了证明 PGC-1a 是一种 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-1α/ERR 相互作用的功能和结构特征。 ERR同种型在介导PGC-1α下游代谢效应中的作用将通过表征功能丧失（ERRa无效小鼠）和功能获得（细胞中ERR同种型的腺病毒过度表达）模型中的代谢表型来确定。该项目的长期目标是确定 PGC-1α/ERR 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子集中的作用。