Dimensions in Endocrine Disruption: Altering Receptor Coregulator Interactions

内分泌干扰的维度：改变受体核心调节器相互作用

基本信息

批准号：
7683063
负责人：
Jillian Rebecca Gunther
金额：
$ 3.49万
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：
2007
资助国家：
美国
起止时间：
2007-09-30 至 2013-09-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7683063
关键词：
Abbreviations Affect Affinity Agonist Agreement Animal Model Attention Benzene Binding Biological Biological Assay Biological Models Boxing Cells Chemicals Chemosensitization Child Complex Data Quality Differentiation and Growth Dimensions Dose Endocrine Endocrine Disruptors Endocrine disruption Endocrine system Energy Transfer Ensure Environment Estrogen Receptors Evaluation Exposure to Family Fluorescein Fluoresceins Fluorescence Fluorescence Resonance Energy Transfer Funding Genetic Transcription Genome Goals Hormone Responsive Hormones Hybrids Hydrazones Hydrophobic Surfaces Individual Interruption Label Laboratories Libraries Ligand Binding Ligand Binding Domain Ligands MYBBP1A gene Measures Metabolism Methodology Modeling Modification Molecular Molecular Bank Molecular Probes Monitor Nuclear Hormone Receptors Nuclear Receptors Pattern Peptides Physiological Process Production Proteins Protocols documentation Pyrimidine Pyrimidines Reagent Receptor Signaling Relative (related person)Reporter Genes Reproducibility Research Resources Screening procedure Secondary to Signal Pathway Signal Transduction Signal Transduction Pathway Site Steroid Receptors Streptavidin Structure Terbium Time Tissues Two-Hybrid System Techniques Universities Woman Work analog base counterscreen design exposed human population high throughput screening in vitro Assay inhibitor/antagonist leucylleucine men novel pharmacophore receptor receptor binding receptor function reproductive response small molecule small molecule libraries time use transcription factor

项目摘要

This project aims to identify possible environmental endocrine disrupters working by an unusual mechanism that operates after the interaction of ligands with nuclear hormone receptors, namely, by the direct inhibition or potentiation of the nuclear hormone receptor/coactivator interaction itself. This goal will be accomplished by developing time-resolved fluorescence assays that probe in a robust and reliable manner the interaction of the nuclear receptors with coactivators. These assays are adaptable to high-throughput screening, and will be used at the Emory University Molecular Libraries Screening Center, an NIH-funded Roadmap Research Resource to which we have obtained access, to identify possible coactivator binding inhibitors (CBIs) or coactivator binding potentiators (CBPs) that might be present in the environment. After compounds have been identified as possible disrupters or potentiators of endocrine function, they will be subject to secondary assays to confirm that they indeed act through these unusual CBI or CBP mechanisms. These assays will also use fluorescence resonance energy transfer methodology, but with carefully selected alterations in the concentrations of integral components to elucidate mechanism. Finally, cell-based assays such as mammalian-2-hybrid, cotransfection reporter gene assays, or monitoring of hormone-responsive gene products will more definitively demonstrate the possible biological or physiological effects arising from exposure to these compounds. This project should help pinpoint a novel endocrine disruption site within the nuclear receptor signaling pathway and identify the compounds that work at this level. It should also help identify possible CBIs or CBPs present in the environment or in commonly used products that could be causing alterations in the pattern of genome transcription by an unusual mechanism, due to the interruption or the potentiation of nuclear receptor-regulated signal transduction that operates at a post ligand-receptor interaction level. Ultimately, this project should help in identifying harmful compounds present within our environment and, hopefully, guide measures to minimize exposure of the public to these substances. Endocrine disrupters are exogenous compounds that interfere with the endocrine system, altering hormone action and the messages it sends throughout the body. This project aims to identify possible endocrine disrupters that act by an unusual mechanism. Large numbers of compounds will be screened to determine structural featurs of those that inhibit or potentiate endocrine action by this unusual process. With this information, steps could be taken to minimize human exposure to these novel types of endocrine disrupters.

该项目旨在确定通过不寻常机制起作用的可能环境内分泌的烦恼在配体与核激素受体相互作用后起作用，即直接抑制或核激素受体/共激活因子本身的增强。这个目标将实现通过开发以鲁棒和可靠的方式探测相互作用的时间分辨荧光测定带有共激活因子的核受体。这些测定可适应高通量筛查，并且将在埃默里大学分子图书馆筛选中心使用，该中心是NIH资助的路线图我们已获得访问的研究资源，以确定可能的共激活抑制剂（CBIS）或共激活器结合增强剂（CBP）可能存在于环境中。化合物后已被确定为内分泌功能的可能的烦恼或增强剂，它们将受到次要测定方法确认它们确实通过这些不寻常的CBI或CBP机制起作用。这些测定还将使用荧光共振能量传递方法，但经过精心选择积分成分浓度的改变以阐明机制。最后，基于细胞的测定例如哺乳动物-2杂交，共转染报告基因测定或激素反应性的监测基因产物将更明确地证明暴露于这些化合物。该项目应有助于查明一个新颖的内分泌干扰站点核受体信号通路并确定在此水平上起作用的化合物。它也应该有帮助确定环境中可能存在的CBI或CBP或可能是常用产品由于中断而导致基因组转录模式的改变或在后配体受体受体的核受体调节信号转导的增强交互水平。最终，该项目应有助于确定我们中存在的有害化合物环境和希望是指导措施，以最大程度地减少公众对这些物质的接触。内分泌不顾问是干扰内分泌系统的外源化合物，改变激素动作及其在整个身体中发送的信息。该项目旨在确定可能的内分泌通过一种不寻常的机制行事的努力。将筛选大量化合物以确定那些通过这种异常过程抑制或增强内分泌作用的结构性特征。与此信息，可以采取步骤来最大程度地减少人类对这些新型内分泌烦恼类型的接触。