Validation of the Estrogen Related Receptor as a therapeutic target in cancer

核受体超家族的几个成员 转录因子参与了线粒体功能的生物发生和/或调节。 更具体地说，包括我们自己在内的许多实验室最近的研究表明，这名孤儿 核受体雌激素受体相关受体-a(ERRA)调节大多数细胞的表达 核编码的基因涉及脂肪酸(3-氧化和氧化磷酸化)。此外, 我们现在有令人信服的数据表明，这种受体参与了对 TCA循环，类固醇合成，胆汁酸代谢，血管生成，己糖一磷酸分流， 线粒体的氨基酸运输，而且它还负向调节脑缺血时的速率限制步骤 糖酵解途径。ERRA活性与线粒体功能的联系重新激发了人们对 该受体亚家族作为癌症、代谢性疾病和线粒体的治疗靶点 营养不良。由于它们在结构上与典型的雌激素受体(era和erp)相似，它 长期以来一直被认为是雌激素反应性的调节因子。现在就是 然而，与ER信号无关的活动似乎也是ERR的一个同样重要的方面 生物学。在这项研究中，我们实验室开发的一系列新技术将被 用于(A)确定Erra在肝脏生物学中的特定角色(S)和(B)确定 不同受体-辅因子复合体的形成与不同的生物学结果有关。 这项工作将提供对这一受体亚类的生理作用的理解，并将 建立科学框架，在此基础上建立旨在发展的发现计划 组织/过程选择性误差调节器。这些目标将在完成后实现。 以下具体目标：目标1：使用定制的方法定义ERRA在肝脏中的生理作用(S) 辅活化子作为蛋白质配基的目标2：鉴定ERRA信号的分子组成 肝脏途径目标3：评估辅因子对Erra转录活性的影响目标4： ERRA差别化演员招募的生物学后果检验(S)：对 共激活剂假说

Several members of the nuclear receptor superfamily of transcription factors have been implicated in the biogenesis and/or regulation of mitochondrial function. More specifically, recent work from many laboratories, including our own, has indicated that the orphan nuclear receptor Estrogen Receptor- Related Receptor-a (ERRa) regulates the expression of most of the nuclear encoded genes involved in fatty acid (3-oxidation and oxidative phosphorylation. In addition, we now have compelling data that indicate that this receptor is involved in the positive regulation of the TCA cycle, steroidogenesis, bile acid metabolism, angiogenesis, the hexose mono-phosphate shunt, mitochondrial amino acid transport, and that it also negatively regulates the rate limiting steps in the glycolytic pathway. The linking of ERRa activity to mitochondrial function has reinvigorated interest in this receptor sub-family as therapeutic targets in cancer, metabolic diseases and mitochondrial dystrophies. Because of their structural similarity to the canonical estrogen receptors (ERa and ERp), it has long been considered that the ERRs function as regulators of estrogen responsiveness. It now appears, however, that activities unrelated to ER signaling are an equally important facet of ERR biology. In this study a series of new technologies, which have been developed in our laboratory, will be used (a) to define the specific role(s) of ERRa in liver biology and (b) to determine whether the formation of different receptor-cofactor complexes are associated with different biological outcomes. This work will provide an understanding of the physiological roles of this receptor subclass and will establish a scientific framework upon which to build discovery programs aimed at developing tissue/process-selective ERR modulators. These objectives will be realized upon completion of the following specific aims: Aim 1: Definition of the physiological role(s) of ERRa in liver using customized coactivators as protein ligands Aim 2: Identification of the molecular components of the ERRa signaling pathways in liver Aim 3: Evaluation of the impact of cofactors on ERRa transcriptional activity Aim 4: Examination of the biological consequence(s) of differential cof actor recruitment by ERRa: A test of the coactivator hypothesis