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

核受体超家族的几个成员 转录因子与线粒体功能的生物发生和/或调节有关。 更具体地说，包括我们自己的实验室在内的许多实验室最近的工作表明， 核受体雌激素受体相关受体-a（ERRa）调节大多数 核编码基因参与脂肪酸β-氧化和氧化磷酸化。此外，本发明还提供了一种方法， 我们现在有令人信服的数据表明，这种受体参与了细胞的正调控， TCA循环，类固醇生成，胆汁酸代谢，血管生成，己糖磷酸分流， 线粒体氨基酸转运，并且它也负调节线粒体氨基酸转运中的限速步骤。 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、代谢疾病和线粒体疾病的治疗靶点， 营养不良由于它们与经典雌激素受体（ER α和ER β）的结构相似， 长期以来一直认为ERRs作为雌激素反应性的调节剂发挥作用。现在 然而，与ER信号无关的活动似乎是ERR的一个同样重要的方面 生物学在这项研究中，一系列的新技术，这已经在我们的实验室开发，将 用于（a）定义ERRa在肝脏生物学中的特定作用和（B）确定ERRa是否 不同受体-辅因子复合物的形成与不同的生物学结果相关。 这项工作将提供对这种受体亚类的生理作用的理解， 建立一个科学框架，在此基础上建立旨在发展的发现计划， 组织/过程选择性ERR调节剂。这些目标将在完成 以下具体目标：目标1：使用定制的ERRa在肝脏中的生理作用的定义 目标2：ERRa信号传导的分子组分的鉴定 目的3：评价辅因子对ERRa转录活性的影响目的4： 通过ERRa检查差异性因子募集的生物学后果： 共激活因子假说

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