Role of Foxa2 in ligand-dependent activation of nuclear receptors

Foxa2 在配体依赖性核受体激活中的作用

• 批准号: 10320019
• 负责人: Irina M. Bochkis
• 金额: $ 40.38万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-10 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10320019
• 关键词: Adverse effects; Affect; Agonist; Atherosclerosis; Bile Acids; Binding; Binding Sites; Cell Nucleus; Cholesterol Homeostasis; Chromatin; Clinical; Clinical Trials; Complex; Congestive Heart Failure; DNA; DNA Binding; Data; Dependence; Development; Diabetes Mellitus; Disease; Distal; Drug Targeting; Dyslipidemias; Family; Fatty Acids; Fracture; Future; Gene Expression; Genes; Genomic approach; Genomics; LXRalpha protein; Ligand Binding; Ligand Binding Domain; Ligands; Liquid substance; Liver; Liver diseases; Malignant Neoplasms; Medical; Metabolic Diseases; Metabolism; Molecular Conformation; Neuraxis; Nuclear Receptors; Nucleosomes; PPAR alpha; PPAR gamma; Patients; Peroxisome Proliferator-Activated Receptors; Pharmaceutical Preparations; Pharmacology; Physiological; Play; Positioning Attribute; Predisposition; Process; Role; Severities; Site; Testing; Thiazolidinediones; Thinking; Transcription Initiation; Up-Regulation; Weight Gain; aged; antagonist; genetic corepressor; glucose metabolism; in vivo; lipid metabolism; mutant; receptor; receptor binding; reduce symptoms; segregation; side effect; transcription factor

Project Summary/Abstract Activation of nuclear receptors, a family of ligand-dependent transcription factors, is used extensively in pharmacology to develop drug targets for diverse medical conditions, including metabolic disease and cancer. While synthetic agonists and antagonists of nuclear receptors ameliorate symptoms of many diseases, clinical use of these compounds leads to frequent side effects that range in their severity. Type II receptors, such as FXR, LXR, and PPAR, which function in fatty acid, bile acid, cholesterol, and glucose metabolism, are permanently positioned in the nucleus regardless of the ligand status. The accepted paradigm regarding ligand activation of type II receptors is a two-step process: 1) the receptor is bound to DNA in complex with a co- repressor in absence of the ligand; 2) binding of the ligand induces a conformational change, co- repressor/co-activator exchange, and initiation of transcription. However, we observe that distribution of open chromatin sites changes upon ligand activation of nuclear receptors. In this project, I hypothesize that pioneer factor Foxa2 modulates chromatin accessibility by evicting nucleosomes to enable LXRα binding upon ligand activation, which challenges the accepted paradigm. Considering current limitations to develop highly selective synthetic ligands for nuclear receptors without significant side effects we propose that a genomic approach that separates LXR targets into distinct regulatory modes characterized by chromatin state and presence/absence of Foxa2 and LXRα binding sites will allow for genes with different physiological function to be targeted separately. We will test whether Foxa2 and LXRα binding is interdependent during ligand activation in Aim 1. We will ascertain the mechanism of Foxa2/LXRα interaction, discriminating between three possibilities in Aim 2. LXR could play the role of a co-activator without binding DNA, or both Foxa2 and LXRα need to be bound either in a proximal interaction or distal interaction. Successful completion of our project will change current thinking regarding activation of ligand-dependent gene expression and change the pharmacological approach to target nuclear receptors essential to metabolism.

项目总结/摘要 核受体的激活，配体依赖性转录因子家族， 广泛的药理学，以开发药物的目标，为不同的医疗条件，包括 代谢疾病和癌症。虽然核受体的合成激动剂和拮抗剂 改善许多疾病的症状，这些化合物的临床使用导致频繁的副作用 影响的严重程度II型受体，如FXR、LXR和PPAR， 在脂肪酸、胆汁酸、胆固醇和葡萄糖代谢中的功能， 无论配体的状态如何关于配体活化的公认范例 II型受体的形成是一个两步过程：1）受体与DNA结合， 阻遏物在缺乏配体的情况下; 2）配体的结合诱导构象变化，共 阻遏物/共激活物交换和转录起始。然而，我们注意到， 开放染色质位点的分布在核受体的配体活化后改变。在这 在这个项目中，我假设先驱因子Foxa 2通过驱逐 核小体，使LXRα结合配体活化，这挑战了公认的 范例 考虑到目前的局限性，开发高选择性的合成配体， 我们提出了一种基因组方法，分离LXR， 靶向不同的调控模式，其特征在于染色质状态和是否存在 Foxa 2和LXRα结合位点将允许具有不同生理功能的基因被整合到基因组中。 分别针对。我们将测试Foxa 2和LXRα的结合是否是相互依赖的， 目标1中的激活。我们将探讨Foxa 2/LXRα相互作用的机制， 目标2中的三种可能性LXR可以发挥共激活剂的作用，而不结合 DNA，或者Foxa 2和LXRα都需要在近端相互作用或远端相互作用中结合。 互动我们的项目的成功完成将改变目前的思维关于激活 配体依赖的基因表达和改变药理学方法靶向核 对新陈代谢至关重要的受体。