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：
7404995
负责人：
Jillian Rebecca Gunther
金额：
$ 3.47万
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/7404995
关键词：
Abbreviations Affect Affinity Agonist Agreement Animal Model Attention Benzene Binding Biological Biological Assay Biological Models Boxing Cells Chemicals Chemosensitization Child Class Complex Data Quality Differentiation and Growth Dimensions Disruption 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 Numbers Pattern Peptides Physiological Process Production Proteins Protocols documentation Pyrimidine Pyrimidines Range Reagent Receptor Signaling Relative (related person)Reporter Genes Reproducibility Research Resources Screening procedure Secondary to Signal Pathway Signal Transduction Signal Transduction Pathway Site Standards of Weights and Measures Steroid Receptors Streptavidin Structure Terbium Thinking Time Tissues Two-Hybrid System Techniques Universities Woman Work analog base 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

Abbreviations Affect Affinity Agonist Agreement Animal Model Attention Benzene Binding Biological Biological Assay Biological Models Boxing Cells Chemicals Chemosensitization Child Class Complex Data Quality Differentiation and Growth Dimensions Disruption 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 Numbers Pattern Peptides Physiological Process Production Proteins Protocols documentation Pyrimidine Pyrimidines Range Reagent Receptor Signaling Relative (related person)Reporter Genes Reproducibility Research Resources Screening procedure Secondary to Signal Pathway Signal Transduction Signal Transduction Pathway Site Standards of Weights and Measures Steroid Receptors Streptavidin Structure Terbium Thinking Time Tissues Two-Hybrid System Techniques Universities Woman Work analog base 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

展开

项目摘要

DESCRIPTION (provided by applicant): 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 features of those that inhibit or potentiated endocrine action by this unusual process. With this information, steps could be taken to minimize human exposure to these novel types of endocrine disrupters.

描述（由申请人提供）：该项目旨在通过一种在配体与核激素受体相互作用后运行的异常机制起作用的可能环境内分泌的烦恼，即通过直接抑制或增强核激素受体/共同激活器的相互作用本身。该目标将通过开发时间分辨的荧光测定法来实现，该测定以可靠且可靠的方式探测核受体与共激活因子的相互作用。这些测定法适用于高通量筛选，并将在埃默里大学分子库筛选中心（NIH资助的路线图研究资源）中使用，我们获得了我们获得的访问，以识别可能存在于环境中的可能存在的结合抑制剂（CBIS）或共同激活抑制剂（CBIS）或共同激活器结合器（CBP）。在将化合物被鉴定为内分泌功能的可能性或增强剂后，它们将受到次要测定的约束，以确认它们确实通过这些异常的CBI或CBP机制作用。这些测定还将使用荧光共振能量传递方法，但是在积分成分浓度中精心选择以阐明机制。最后，基于细胞的测定如哺乳动物-2-杂化，共转染报告基因测定或对激素反应性基因产物的监测将更明确地证明暴露于这些化合物而产生的生物学或生理效应。该项目应有助于查明核受体信号通路内的新内分泌破坏部位，并确定在此水平上起作用的化合物。它还应有助于确定环境中存在的CBI或CBP或可能导致通过异常机制在基因组转录模式变化的常用产品中，由于核受体受调节信号转导的中断或增强，该信号转导在后体和受体受体相互作用水平上起作用。最终，该项目应有助于确定我们环境中存在的有害化合物，并希望指导措施将公众接触到这些物质。内分泌不顾问是干扰内分泌系统的外源化合物，改变了激素作用及其在整个身体中发送的信息。该项目旨在确定通过异常机制起作用的可能内分泌的烦恼。将筛选大量化合物，以确定通过这种异常过程抑制或增强内分泌作用的结构特征。有了这些信息，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。