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. ? ?
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