DESIGNING CHEMICAL PROBES TO EXPLORE HORMONE ACTION

虽然靶向糖皮质激素受体（GR）的配体具有许多靶向糖皮质激素受体（GR）的功能，但其在糖皮质激素受体（GR）中的作用并不明显。 潜在的令人兴奋的应用，它们的使用受到严重的限制 副作用. 副作用可能是由于受体作用于 不同类别的响应元素。 糖皮质激素受体 显示了不同的转录调控效应，这取决于 糖皮质激素反应元件（GRE）的特异性DNA序列 以及其他细胞因子的存在。 的 本项目的目的是确定激素的作用 这种差异化的行为。 各种糖皮质激素 将合成具有独特结构性质的配体， 在报告基因测定中用不同类别的GRES进行测试， 各种细胞因子。 虽然激素结合结构域的结构， 糖皮质激素受体尚未确定，糖皮质激素受体的结构模型 该结构域基于诱变数据和与其它激素同源性 受体已使用计算机图形实验室的资源。 通过将该模型与报告基因测定结合使用， 配体结构如何影响转录的结构图 规则可以确定。 这些信息可能是 在设计更有效的糖皮质激素激动剂方面非常有用， 对手。

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.