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：
8121655
负责人：
Jillian Rebecca Gunther
金额：
$ 3.87万
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 2012-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8121655
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 Fluorescence Fluorescence Resonance Energy Transfer Funding Genetic Transcription Genome Goals Hormone Responsive Hormones Hybrids Hydrazones Hydrophobic Surfaces Individual Interruption Label Laboratories Ligand Binding Ligand Binding Domain Ligands Measures Metabolism Methodology Modeling Modification Molecular Bank Molecular Probes Monitor Nuclear Hormone Receptors Nuclear Receptors Pattern Peptides Physiological Process Production Proteins Protocols documentation 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 United States National Institutes of Health 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.

该项目旨在识别可能通过不寻常机制发挥作用的环境内分泌干扰物在配体与核激素受体相互作用后起作用，即通过直接抑制或核激素受体/共激活剂相互作用本身的增强。这个目标将会实现通过开发时间分辨荧光测定法，以稳健可靠的方式探测相互作用核受体与共激活剂。这些测定法适用于高通量筛选，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权的研究资源，以确定可能的共激活剂结合抑制剂环境中可能存在的（CBI）或共激活剂结合增强剂（CBP）。复合后已被确定为内分泌功能的可能干扰物或增强物，它们将受到二次测定以确认它们确实通过这些不寻常的 CBI 或 CBP 机制发挥作用。这些测定也将使用荧光共振能量转移方法，但经过仔细选择改变整体成分的浓度以阐明机制。最后，基于细胞的检测例如哺乳动物 2 杂交、共转染报告基因检测或激素反应监测基因产物将更明确地证明可能产生的生物或生理效应接触这些化合物。该项目应有助于确定体内一个新的内分泌干扰位点核受体信号通路并鉴定在该水平起作用的化合物。应该也有帮助识别环境中或常用产品中可能存在的 CBI 或 CBP 由于中断，通过不寻常的机制引起基因组转录模式的改变或在后配体受体上起作用的核受体调节信号转导的增强交互级别。最终，这个项目应该有助于识别我们体内存在的有害化合物环境，并希望能够指导采取措施，尽量减少公众接触这些物质。内分泌干扰物是干扰内分泌系统、改变激素的外源性化合物动作及其向全身传递的信息。该项目旨在确定可能的内分泌通过不寻常机制发挥作用的破坏者。将筛选大量化合物以确定通过这种不寻常的过程抑制或增强内分泌作用的结构特征。有了这个根据信息，可以采取措施尽量减少人类接触这些新型内分泌干扰物。