GENE REGULATION BY STEROID RECEPTOR PROTEINS

描述（由申请人提供）：该项目的长期目标是定义后生动物的转录调控机制，了解调控因子如何指定基因表达程序作为发育，细胞或生理线索的功能，并破译基因调控回路。一般策略是在哺乳动物细胞中鉴定受细胞内受体（IR）超家族成员直接调节的靶基因，如糖皮质激素受体。通过比较这些靶基因亚群的调控机制，将定义调控复合物的选择性组装和拆卸的决定因素；反过来，这些复合物将被研究以阐明信号和调控机制。具体目标是定义IR调节复合物的结构、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节网络中信号通路整合的纽带。设想有四个目标：(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调节复合物调控转录的分子机制；(3)确定小分子配体如何指定IRs的功能表面；(4)确定IR调节复合物的分解机制。IR与多种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，而IR配体是最常用的治疗药物。因此，了解IR作用的原理和机制对健康以及疾病的检测、治疗和治愈具有重要意义。

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.