GENE REGULATION BY STEROID RECEPTOR PROTEINS

类固醇受体蛋白的基因调控

• 批准号: 7029856
• 负责人: KEITH Robert YAMAMOTO
• 金额: $ 63.87万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 1976
• 资助国家: 美国
• 起止时间: 1976-12-01 至 2010-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7029856
• 关键词: Caenorhabditis elegans; DNA binding protein; X ray crystallography; acyltransferase; allosteric site; androgen receptor; chromatin; corticosteroid receptors; crystallization; gene expression; genetic regulation; genetic regulatory element; genetically modified animals; glucocorticoids; histones; hormone receptor; hormone regulation /control mechanism; laboratory mouse; ligands; protein protein interaction; protein structure function; receptor binding; thyroid hormones; transcription factor; yeast two hybrid system

DESCRIPTION (provided by applicant): The long term objectives of this project are to define mechanisms of transcriptional regulation in metazoans, to understand how a regulatory factor specifies programs of gene expression as a function of developmental, cellular or physiological cues, and to decypher gene regulatory circuits. The general strategy is to identify in mammalian cells target genes that are directly regulated by members of the intracellular receptor (IR) superfamily, such as the glucocorticoid receptor. By comparing the regulatory machinery at subsets of those target genes, determinants of selective assembly and disassembly of regulatory complexes will be defined; in turn, the complexes will be probed to elucidate signaling and regulatory mechanisms. The specific aims are to define key aspects of the structure, mechanisms, dynamics and combinatorial selectivities of IR regulatory complexes, and how they serve as nexus for integration of signaling pathways in regulatory networks. Four goals are envisioned: (1) define determinants of composition and architecture for assembly of IR regulatory complexes; (2) determine molecular mechanisms by which IR regulatory complexes modulate transcription; (3) determine how small molecule ligands specify functional surfaces of IRs; (4) determine mechanisms of disassembly of IR regulatory complexes. IRs have been implicated in a wide range of diseases and developmental disorders, including cancer, diabetes, osteoporosis, hypertension and inflammation, and IR ligands are the most heavily prescribed therapeutics. Thus, understanding the principles and mechanisms of IR action has important implications for health, and for detecting, treating and curing disease.

描述（由申请人提供）：本项目的长期目标是确定后生动物中的转录调控机制，了解调控因子如何指定基因表达程序作为发育、细胞或生理线索的函数，并破译基因调控回路。一般的策略是在哺乳动物细胞中鉴定直接受细胞内受体（IR）超家族成员（如糖皮质激素受体）调节的靶基因。通过比较这些靶基因的子集的调节机制，调节复合物的选择性组装和拆卸的决定因素将被定义;反过来，复合物将被探测以阐明信号传导和调节机制。具体目标是定义IR调控复合物的结构、机制、动力学和组合选择性的关键方面，以及它们如何作为调控网络中信号通路整合的纽带。设想了四个目标：（1）确定IR调节复合物组装的组成和结构的决定因素;（2）确定IR调节复合物调节转录的分子机制;（3）确定小分子配体如何指定IR的功能表面;（4）确定IR调节复合物的分解机制。IR与广泛的疾病和发育障碍有关，包括癌症、糖尿病、骨质疏松症、高血压和炎症，并且IR配体是最常用的治疗剂。因此，了解IR作用的原理和机制对健康以及检测、治疗和治愈疾病具有重要意义。