Project 2: An Integrated Experimental and Computational Approach to Understand t

项目 2：一种理解 t 的综合实验和计算方法

• 批准号: 8829252
• 负责人: Russell S Thomas
• 金额: $ 27.74万
• 依托单位: MICHIGAN STATE UNIVERSITY
• 依托单位国家: 美国
• 资助国家: 美国
• 起止时间: 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829252
• 关键词: Accounting; Address; B cell differentiation; B-Lymphocytes; Behavior; Biological; CD40 Ligand; Chemical Models; Chemicals; Chromosome Mapping; Computer Simulation; Data; Data Analyses; Dioxins; Dose; Drug Kinetics; Economics; Embryo; Eye; Female; Functional disorder; Gene Expression; Gene Expression Microarray Analysis; Genes; Genetic Heterogeneity; Goals; Grant; Hazardous Waste Sites; Hormones; Human; Immunoglobulin M; Immunosuppression; In Vitro; Inbred Mouse; Inbred Strain; Inbred Strains Mice; Incidence; Individual; Instruction; Knowledge; Ligands; Literature; Maps; Measures; Mediating; Methods; Modeling; Mus; National Research Council; Non-linear Models; Pathway interactions; Persons; Physiological; Population; Pregnancy; Process; Public Health; QTL Genes; Quantitative Trait Loci; Recommendation; Reporting; Research; Resistance; Risk Assessment; Role; Science; Serum; Shapes; Site; Steroids; Superfund; System; Testing; Tetrachlorodibenzodioxin; Tissues; Toxic effect; base; behavioral response; cancer risk; follow-up; human population genetics; implantation; in vitro Model; in vivo; in vivo Model; microbial; phenome; population based; pregnant; programs; receptor; remediation; response; sound; steroid hormone; superfund site; toxicant; trait

PROJECT SUMMARY (See Instructions); A recent report released by the National Research Council (NRC) entitled "Science and Decisions" has suggested that in cases where there is a background incidence of a dysfunction which is augmented by a toxicant, human variability would effectively linearize the population dose-response curve even if the dose response curve in an individual person was non-linear or showed a threshold. The arguments for linearization of the dose-response curve due to human variability are largely theoretical with a limited amount of experimental data and the use of a threshold approach for non-cancer endpoints has been standard practice in chemical risk assessment for decades. Changing to a linear, no threshold approach would have a major impact on clean up levels at Superfund sites and any decision to replace the traditional threshold approach for non-cancer endpoints should be based on sound science with adequate experimental data 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is widely accepted to act through a receptor-mediated mode-of action with an associated non-linear dose response. We propose to use TCDD as a model chemical to experimentally evaluate the ideas laid out in the NRC report. The primary hypothesis of the project is that characterization of the dose-response curves for the immunosuppression and embryotoxicity of TCDD will demonstrate that the response is consistent with a non-linear model and the incorporation of population variability will not linearize the population-based dose-response curve in the manner proposed by the NRC. This hypothesis will be tested using a panel of inbred mice that provides an In vivo model of the genetic heterogeneity in the human population and an in vitro human model. The specific aims of this proposal are: (1) evaluate the effects of genetic heterogeneity on the population dose-response curve for TCDD-mediated embryotoxicity and serum hormone alterations using the Mouse Phenome Diversity Panel of inbred mice as a model; (2) evaluate the effects of human inter-individual variability on the population dose-response curve for TCDD-mediated suppression of B-cell IgM secretion; (3) Identify and characterize the genes and pathways associated with the inter-strain differences in TCDD-mediated embryotoxicity to understand the mode-of-action. Computational models of TCDD-mediated embryotoxicity and B-cell suppression will be constructed and used to understand behavior of the system at low, environmentally-relevant doses. Through these specific aims, a substantial amount of scientific data and analysis will be generated across multiple non-cancer endpoints (early embryotoxicity, steroid hormone alterations, and B-cell immunosuppression), in two different species (mice and humans), and using both in vivo and in vitro models to evaluate the assumption underlying the NRC report.

项目摘要（请参阅说明）； 国家研究委员会（NRC）发表的一份题为“科学与决策”的最新报告表明，如果有毒物增强功能障碍的背景发生率，那么人类的可变性也会有效地线性地线性地线性地线性化，即使个人的剂量响应曲线在个体中的剂量响应曲线也不是线性的或表现出斜度。由于人类可变性而导致的剂量反应曲线的线性化论点在很大程度上是理论上的，并且实验数据数量有限，并且用于非癌症终点的阈值方法已成为数十年来化学风险评估的标准实践。更改为线性，没有阈值方法将对超级基金站点的清理水平产生重大影响，任何决定取代非癌症终点的传统阈值方法的决定都应基于合理的科学，并具有足够的实验数据2,3,7,8-Tetrachlorodibenzo-p-dioxin（tcdd），从而通过受体模式与不相关的模式进行响应。我们建议将TCDD用作模型化学物质，以实验评估NRC报告中提出的想法。该项目的主要假设是，TCDD的免疫抑制和胚胎毒性的剂量反应曲线的表征将表明，该响应与非线性模型一致，并且人口变异性的结合不会使基于人群的剂量 - 剂量 - 反应曲线在NRC提出的方式中线性化。该假设将使用一组近交小鼠面板进行检验，该小鼠提供了人群中遗传异质性和体外人类模型的体内模型。该提案的具体目的是：（1）评估遗传异质性对TCDD介导的胚胎的胚胎毒性和血清激素改变的影响，使用近育小鼠作为模型的小鼠现象多样性面板的影响； （2）评估人类间变异性对TCDD介导的B细胞IgM分泌抑制的人群剂量响应曲线的影响； （3）识别并表征与TCDD介导的胚胎毒性相关的基因和途径，以了解行动方式。 TCDD介导的胚胎毒性和B细胞抑制的计算模型将被构建，并用于理解系统低，环境与环境相关的剂量的行为。通过这些具体目的，将在多个非癌终点（早期胚胎毒性，类固醇激素的改变和B细胞免疫抑制）中生成大量的科学数据和分析，在两个不同的物种（小鼠和人类）中，以及使用体内和体外模型来评估NRC报告的假设。