Mechanisms of regulation of LRH-1, Nanog and SF-1 by DAX-1

DAX-1对LRH-1、Nanog和SF-1的调节机制

基本信息

批准号：
7756405
负责人：
ROBERT J FLETTERICK
金额：
$ 4.84万
依托单位：
UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-12-10 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7756405
关键词：
Adrenal Glands Adrenal gland hypofunction Affect Animal Welfare Applications Grants Bibliography Bile Acid Biosynthesis Pathway Binding Biochemical Biological Assay Budgets Cells Characteristics Cholesterol Homeostasis Code Collaborations Complement Complex Congenital Adrenal Hypoplasia Consult Country DNA DNA Binding Domain DNA Damage Defect Development Developmental Process Disease Educational process of instructing Embryonic Development Endocrine Endocrine Syndrome Endocrine System Diseases Endocrine system Environment Environmental Impact Equipment Experimental Designs Family Female Fibrinogen Foundations Funding Gender Gene Targeting Genes Genetic Genetic Transcription Goals Grant Health Holly Homologous Gene Hormones Human Human Resources Hypothalamic structure IACUC Infertility Inherited International Learning Length Letters Life Link Liver Maintenance Malignant Neoplasms Malignant neoplasm of testis Medical Mental Health Metabolic Diseases Methods Molecular Biology Mutation NR0B1 gene Names Neurosecretory Systems Nuclear Orphan Receptor Nuclear Receptors Orphan Ovary Participant Pathway interactions Pharmaceutical Preparations Phenotype Physiological Pituitary Gland Preparation Principal Investigator Process Protein Binding Proteins Protocols documentation Regulation Relative (related person)Research Research Ethics Committees Resolution Resources Role Screening procedure Structural Models Structure Syndrome System Testing Testis Therapeutic Intervention Time Tissues Transcriptional Activation United States National Institutes of Health Update Vertebrates Work X Chromosome X-Ray Crystallography abstracting base derepression design dosage embryonic stem cell experience expiration gene repression homeodomain human subject in vitro Assay member molecular pathology mutant novel pluripotency programs protein complex receptor research study sex steroid hormone biosynthesis success three dimensional structure transcription factor

项目摘要

Nuclear receptors program many endocrine processes essential for health and life. Among the most enigmatic are those receptors, which are critically important but have unknown regulating hormones, such as DAX-1, LRH-1 and SF-1. These are the targets of this proposal. Medical disorders teach us about the interplay of these receptors in the endocrine system without telling us their mechanisms. The DAX-1 gene codes an unusual nuclear receptor lacking a DNA interaction domain. Yet it controls the activity of many target genes in many tissues. Mutations in DAX-1 affect embryonic stem cell progression, development of the adrenal and pituitary glands, the hypothalamus and the ovaries or testes leading to severe endocrine disorders. The receptors LRH-1 and SF-1 are critical in developmental processes, and their constitutive activation is muted by DAX-1. These three nuclear receptors and transcription factors are called orphans because their controlling hormones, if they exist, have not been identified. The most basic details of the mechanisms of regulation of these related nuclear receptors are not known. The goal of this proposal is to understand the principles and atomic level details of the mechanisms of regulation of LRH-1 and SF-1 by DAX-1. Since it halts transcriptional activation, DAX-1 may be classed as a co-repressor with unknown hormone. Because regulation by DAX-1 depends on the associations of these proteins we will analyze, at atomic resolution, the binding interactions of DAX-1 with LRH-1 and SF-1. DAX-1 protein, which has never been prepared in a functionally active state for either biochemical or structural studies, will be isolated and crystallized with LRH-1 and SF-1 so that three-dimensional structures of the assemblies may be analyzed. Functional studies guided by the structural models will carried out in cells to reveal the mechanisms of action of these receptors. This information will be the foundation for understanding the molecular pathology of numerous human endocrine syndromes and suggest pathways for therapeutic intervention. The nuclear receptors we are studying are associated with many disease processes, including cancer, infertility, genetic metabolic diseases, and mental health defects. Learning the mechanisms of action of these receptors, and what goes wrong in the diseases, will help suggest pathways for design of new drug treatments for these conditions.

核受体调节许多对健康和生命至关重要的内分泌过程。其中最神秘的是那些受体，它们至关重要，但具有未知的调节激素，例如 DAX-1、LRH-1 和 SF-1。这些是本提案的目标。医学疾病让我们了解内分泌系统中这些受体的相互作用，但没有告诉我们它们的机制。 DAX-1 基因编码一种不寻常的核受体，缺乏 DNA 相互作用结构域。然而它控制许多组织中许多靶基因的活性。 DAX-1 突变会影响胚胎干细胞的进展、肾上腺和垂体、下丘脑以及卵巢或睾丸的发育，从而导致严重的内分泌紊乱。受体 LRH-1 和 SF-1 在发育过程中至关重要，它们的组成性激活被 DAX-1 抑制。这三种核受体和转录因子被称为孤儿，因为它们的控制激素（如果存在的话）尚未被识别。这些相关核受体调节机制的最基本细节尚不清楚。该提案的目标是了解 DAX-1 调节 LRH-1 和 SF-1 的机制的原理和原子级细节。由于 DAX-1 可以阻止转录激活，因此它可以被归类为未知激素的共阻遏物。由于 DAX-1 的调节取决于这些蛋白质的关联，我们将以原子分辨率分析 DAX-1 与 LRH-1 和 SF-1 的结合相互作用。 DAX-1 蛋白从未以功能活性状态制备用于生化或结构研究，将用 LRH-1 和 SF-1 进行分离和结晶，以便分析组件的三维结构。以结构模型为指导的功能研究将在细胞中进行，以揭示这些受体的作用机制。这些信息将成为理解多种人类内分泌综合征的分子病理学的基础，并提出治疗干预的途径。我们正在研究的核受体与许多疾病过程相关，包括癌症、不孕症、遗传代谢疾病和心理健康缺陷。学习作用机制这些受体以及疾病中出现的问题将有助于为这些疾病的新药物治疗设计提供思路。