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

验证雌激素相关受体作为癌症治疗靶点

• 批准号: 8012324
• 负责人: Donald P McDonnell
• 金额: $ 8.93万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-02-04 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012324
• 关键词: Address; Adopted; Affinity; Agonist; Agreement; Animal Model; Animal Welfare; Bibliography; Biogenesis; Biology; Boxing; Breast Cancer Cell; Cell Line; Cell Respiration; Cell model; Cells; Citric Acid Cycle; Complex; Country; Data; Data Set; Disease Outcome; ERBB2 gene; Engineering; Environment; Environmental Impact; Enzymes; Epithelial Cells; Equipment; Estrogen Antagonists; Estrogen Receptor Modulators; Estrogen Receptors; Estrogens; Family; Functional disorder; Gene Activation; Gene Expression; Gene Expression Profile; Gene Targeting; Generations; Genes; Goals; Grant; Human; IACUC; Impact evaluation; Intention; International; Lead; Left; Ligand Binding; Ligands; Link; MCF7 cell; Malignant Neoplasms; Mammary Neoplasms; Mammary gland; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Molecular Conformation; Nuclear Receptors; Orphan; Outcome; Paper; Pathway interactions; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Principal Investigator; Process; Proteins; Published Comment; Publishing; Research; Research Ethics Committees; Research Personnel; Resources; Role; Signal Transduction; Small Interfering RNA; Stream; Suggestion; Surface; Technology; Testing; Time; Tumor Pathology; Validation; Vertebrates; Work; abstracting; base; cofactor; combinatorial; estrogen-related receptor; expiration; fatty acid oxidation; human subject; malignant breast neoplasm; meetings; mutant; outcome forecast; overexpression; programs; receptor; receptor function; research study; response; success; therapeutic target; tumor

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

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，包括我们自己在内的许多实验室的最新工作表明孤儿 核受体雌激素受体相关受体A（ERRA）调节大多数的表达 参与脂肪酸的核编码基因（3-氧化和氧化磷酸化。此外， 现在，我们拥有令人信服的数据，表明该受体参与了的正调节 TCA循环，类固醇生成，胆汁酸代谢，血管生成，己糖单磷酸分流， 线粒体氨基酸的转运，并且还负责调节速率限制步骤 糖酵解途径。 ERRA活性与线粒体功能的联系引起了人们对 该受体作为癌症，代谢性疾病和线粒体的治疗靶标的亚家族。 营养不良。由于它们与规范雌激素受体（ERA和ERP）的结构相似性， 长期以来，人们一直认为，错误是雌激素反应能力的调节剂。现在 但是，似乎与ER信号无关的活动是ERR同样重要的方面 生物学。在这项研究中，我们的实验室中开发的一系列新技术将是 使用（a）定义ERRA在肝生物学中的特定作用，以及（b）确定是否是否 不同受体配合物复合物的形成与不同的生物学结果有关。 这项工作将提供对该受体亚类的生理作用的理解，并将 建立一个科学框架，以建立旨在开发的发现计划 组织/过程选择性错误调节器。这些目标将在完成后实现 以下特定目的：目标1：使用自定义 共激活因子作为蛋白质配体目标2：识别ERRA信号的分子成分 肝脏目标3：评估辅因子对ERRA转录活动的影响目标4： 检查ERRA的差异COF参与者招募的生物学后果：测试 共激活因子假设