类固醇受体分子探针-猫眼课题宝

类固醇受体分子探针

批准号：

8010991

负责人：

JOHN A. KATZENELLENBOGEN

金额：

$12.67万

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：

2010

资助国家：

美国

项目状态：

已结题

起止时间：

2010-01-15 至 2010-12-31

来源：

https://reporter.nih.gov/project-details/8010991

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

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中文摘要

翻译

本项目的目的是(1)了解雌激素的各种药理作用的分子基础，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-辅活化子相互作用发挥作用的新型雌激素作用抑制剂；(3)制备可用于研究配体如何在全基因组基础上调节核受体-辅调节器相互作用的蛋白质微阵列。我们将应用先进的荧光方法来研究雌激素受体ERA和ERI3的构象动力学和相互作用，以及它们与辅助调节蛋白的相互作用，以及这些作用是如何被各种ER配体调节的，包括我们开发的ER亚型选择性配体。具体的研究将集中在蛋白质构象动力学和相互作用在这些过程中的作用相互作用，共激活子和辅抑制子的招募竞争，SERM如他莫昔芬的激动性，以及ERC_.ERI3异二聚体功能的配体调节。利用基于结构的从头设计，我们将开发小分子共激活剂结合抑制剂。这应该会在与抗雌激素不同的水平上阻止雌激素的作用，并可能克服乳腺癌的抗雌激素耐药性。将开发核激素受体或辅助调节因子的蛋白质微阵列，以分析受体-辅助调节因子相互作用的配体调节。快速、高通量、全基因组方式。该项目将有助于更好地了解雌激素作用的分子基础，调节雌激素活性的新药物，以及发现新的雌激素和其他核受体配体的有力工具。

英文摘要

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.

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