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MOLECULAR PROBES FOR STEROID RECEPTORS

类固醇受体分子探针

基本信息

批准号：
7904242
负责人：
JOHN A. KATZENELLENBOGEN
金额：
$ 36.11万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-09-01 至 2013-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7904242
关键词：
Agonist Area Authorization documentation Back Binding Binding Proteins Biocompatible Materials Biological Assay Biology Chemicals Contracts Development Disclosure Environment Estrogen Antagonists Estrogen Receptor Modulators Estrogen Receptors Estrogens Face Fluorescence Fluorescence Resonance Energy Transfer Funding Generations Genome Glass Goals Grant Human Resources Illinois Instruction Investigation Last Name Lead Length Ligand Binding Ligand Binding Domain Ligands Methodology Methods Molecular Molecular Models Molecular Probes Names Nuclear Hormone Receptors Nuclear Receptors Organ Pharmacology Principal Investigator Printing Progress Reports Protein Dynamics Protein Microchips Proteins Regulation Research Research Project Grants Resistance Role Selective Estrogen Receptor Modulators Signal Transduction Site Slide Steroid Receptors Structure System Tamoxifen Techniques Trustees United States National Institutes of Health Universities Vision Work base combinatorial design drug discovery fluorophore genome-wide high throughput screening improved in vivo inhibitor/antagonist luminescence resonance energy transfer malignant breast neoplasm molecular modeling novel programs promoter protein protein interaction receptor receptor density receptor function small molecule tool

项目摘要

The aims of this project are (1) to understand the molecular basis of the diverse pharmacology of estrogens, including the selective estrogen receptor modulators (SERMs) and antiestrogens, (2) to develop novel inhibitors of estrogen action that act by blocking receptor-coactivator interactions, and (3) to prepare protein microarrays that can be used to study how ligands regulate nuclear receptor-coregulator interactions on a genome-wide basis. We will apply advanced fluorescence methodologies to study the conformational dynamics and interactions of the estrogen receptors ERa and ERI3 and their interactions with coregulator proteins and how these are modulated by various ER ligands, including the ER subtype-selective ligands we have developed. Specific studies will focus on the role of protein conformational dynamics and reciprocity in these interactions, competition in recruitment of coactivators vs. corepressors, the agonism of SERMs such as tamoxifen, and ligand regulation of the function of ERc_.ERI3 heterodimers. Using structure-based and de novo design, we will develop small molecule coactivator binding inhibitors that should block estrogen action at a different level than antiestrogens and might overcome antiestrogen resistance in breast cancer. Protein microarrays of nuclear hormone receptors or coregulators will be developed to assay ligand regulation of receptor-coregulator interaction in a rapid, high throughput, genome-wide manner. This project should lead to improved understanding of the molecular basis of estrogen action, novel agents to regulate estrogen activity, and powerful tools for the discovery of novel estrogens and other ligands for nuclear receptors.

该项目的目的是（1）了解雌激素的不同药理学的分子基础，包括选择性雌激素受体调节剂（SERM）和抗雌激素，（2）开发通过阻断受体-辅激活剂相互作用发挥作用的新型雌激素作用抑制剂，以及（3）制备蛋白质微阵列，其可用于研究配体如何在全基因组基础上调节核受体-辅调节因子相互作用。我们将应用先进的荧光方法来研究雌激素受体ERa和ERI 3的构象动力学和相互作用及其与辅调节蛋白的相互作用，以及这些如何受到各种ER配体（包括我们开发的ER亚型选择性配体）的调节。具体的研究将集中在蛋白质构象动力学的作用和互惠在这些相互作用、共激活子相对于共阻遏子的募集中的竞争、SERMs如他莫昔芬的激动作用和ERc_ER13异二聚体的功能的配体调节。利用基于结构和从头设计，我们将开发小分子辅激活因子结合抑制剂这应该在不同水平上阻断雌激素作用，而不是抗雌激素，并可能克服乳腺癌中抗雌激素抵抗。将开发核激素受体或辅调节因子的蛋白质微阵列，以测定配体对受体-辅调节因子相互作用的调节，快速、高通量、全基因组的方式。该项目将导致对雌激素作用的分子基础的更好理解，调节雌激素活性的新型药物，以及发现新型雌激素和其他核受体配体的强大工具。