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

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）：该项目旨在识别可能的环境内分泌干扰物，其通过一种不寻常的机制起作用，该机制在配体与核激素受体相互作用后起作用，即通过直接抑制或增强核激素受体/共激活剂相互作用本身。这一目标将通过开发时间分辨荧光测定来实现，该测定以稳健可靠的方式探测核受体与共激活剂的相互作用。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（我们已获得 NIH 资助的路线图研究资源）使用，以鉴定可能的共激活剂结合抑制剂 (CBI) 或共激活剂结合增强剂（CBP）可能存在于环境中。在化合物被确定为内分泌功能的可能干扰剂或增强剂后，将对它们进行二次测定，以确认它们确实通过这些不寻常的 CBI 或 CBP 机制发挥作用。这些测定还将使用荧光共振能量转移方法，但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基因产物的监测，将更明确地证明暴露于这些化合物可能产生的生物或生理效应。该项目应有助于查明核受体信号通路内的一个新的内分泌干扰位点，并确定在该水平上发挥作用的化合物。它还应该有助于识别环境中或常用产品中可能存在的 CBI 或 CBP，这些 CBI 或 CBP 可能通过不寻常的机制导致基因组转录模式的改变，这是由于核受体调节信号转导的中断或增强所致。在配体-受体相互作用后水平。最终，该项目应有助于识别我们环境中存在的有害化合物，并有望指导采取措施，最大限度地减少公众接触这些物质。内分泌干扰物是干扰内分泌系统、改变激素作用及其在全身传递的信息的外源性化合物。该项目旨在识别通过不寻常机制发挥作用的可能内分泌干扰物。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化合物的结构特征。有了这些信息，就可以采取措施尽量减少人类接触这些新型内分泌干扰物。