DESIGNING CHEMICAL PROBES TO EXPLORE HORMONE ACTION

点击翻译按钮获取中文摘要

While ligands targeting the glucocorticoid receptor (GR) have many potentially exciting applications, their use is limited by serious side effects. The side effects could be due to the receptor acting at distinct classes of response elements. The glucocorticoid receptor shows different regulatory effects on transcription depending on the specific DNA sequence of the glucocorticoid response element (GRE) that it binds as well as the presence of other cellular factors. The purpose of this project is to determine the effect of hormone structure on this differential behavior. Various glucocorticoid ligands with unique structural properties will be synthesized and tested in reporter gene assays with the different classes of GREs and various cellular factors. Although the structure of the hormone binding domain of the glucocorticoid receptor has not been determined, a structural model of the domain based on mutagenesis data and homology to other hormone receptors has been made using Computer Graphics Laboratory resources. By using this model in conjunction with the reporter gene assays, a structural picture for how ligand structure influences transcriptional regulation can be determined. This information could potentially be very useful in designing more effective glucocorticoid agonists and antagonists.