GENE REGULATION BY STEROID RECEPTOR PROTEINS

这个项目的长期目标是了解后生动物的转录调控，以及调控因子可以指定不同程序的基因表达作为发育或生理线索的功能的机制。拟议研究的总体策略是分析细胞内受体（IR）超家族成员的调控，其中包括类固醇、甲状腺激素、类维生素A和其他小的亲脂性配体的受体。组合调控可能反映了多因子调控复合物的受控组装，其组分和功能依赖于环境。因此，IR调节复合物在不同背景下的组装和功能将被机械地解剖，从纯蛋白质到整个生物体的设置。本研究的具体目的是表征IR调节复合物的结构和活性的条件下，其中的配体（定义一个细胞特异性的上下文）或响应元件（定义一个基因特异性的上下文）是不同的复合物内。 设想了四个目标：（1）确定功能不同的调节复合物是如何由配体指定的;（2）确定基因特异性调节复合物和IR功能是如何由反应元件指定的;（3）确定受体与Swi/Snf染色质重塑复合物相互作用的结构和意义;（4）研究简单后生动物C.优雅在这些实验中，分子遗传学，生物化学和结构的方法将被用来确定功能表面和相互作用的因素，指定转录激活，抑制，复合调控和协同作用在体外，在细胞和整个动物。IR与癌症、高血压和炎症等多种疾病有关，IR配体被广泛用作治疗剂、诊断剂和化学预防剂。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。

The long term objectives of this project are to understand metazoan transcriptional regulation, and mechanisms by which a regulatory factor can specify different programs of gene expression as a function of developmental or physiological cues. The general strategy of the proposed research is to analyze regulation by members of the intracellular receptor (IR) superfamily, which includes receptors for steroids, thyroid hormone, retinoids, and other small lipophilic ligands. Combinatorial regulation likely reflects the controlled assembly of multifactor regulatory complexes, whose components and functions are context-dependent. Thus, the assembly and functions of IR regulatory complexes in different contexts will be dissected mechanistically, in settings ranging from pure proteins to whole organisms. The specific aims of the present study are to characterize the structure and activities of IR regulatory complexes under conditions in which the ligand (which defines a cell-specific context) or the response element (which defines a gene-specific context) are varied within the complexes. Four goals are envisioned: (1) determine how functionally distinct regulatory complexes are specified by ligands; (2) determine how gene-specific regulatory complexes and IR functions are specified by response elements; (3) determine the structure and significance of receptor interactions with Swi/Snf chromatin remodeling complexes; (4) investigate IR regulatory complex formation and function in the simple metazoan C. elegans. In these experiments, molecular genetic, biochemical and structural approaches will be used to identify functional surfaces and interacting factors that specify transcriptional activation, repression, composite regulation and synergy in vitro, in cells and in whole animals. IRs have been implicated in a wide range of diseases, including cancer, hypertension and inflammation, and IR ligands are widely used as therapeutics, diagnostics and chemopreventatives. Thus, understanding the principles and mechanisms of IR action has important implications for health, and for detecting, treating and curing disease.