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（参见说明）； 国家研究委员会 (NRC) 最近发布的一份题为“科学与决策”的报告表明，在存在因有毒物质而加剧的功能障碍的背景发生率的情况下，人类变异性将有效地使人群剂量反应曲线线性化即使个体的剂量反应曲线是非线性的或显示出阈值。由于人类变异性而导致剂量反应曲线线性化的论点很大程度上是基于有限数量的实验数据的理论，并且使用非癌症终点阈值方法已成为数十年来化学风险评估的标准做法。更改为线性、无阈值方法将对超级基金地点的清理水平产生重大影响，任何取代非癌症终点的传统阈值方法的决定都应基于可靠的科学和足够的实验数据2,3,7， 8-四氯二苯并-对-二恶英 (TCDD) 被广泛认为通过受体介导的作用模式发挥作用，并具有相关的非线性剂量反应。我们建议使用 TCDD 作为模型化学品来通过实验评估 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证明该反应与非线性模型一致，并且群体变异性的纳入不会使基于群体的剂量线性化。按照 NRC 提议的方式绘制响应曲线。该假设将使用一组近交小鼠进行测试，这些小鼠提供了人群遗传异质性的体内模型和体外人类模型。本提案的具体目的是：（1）以近交系小鼠表型多样性面板为模型，评估遗传异质性对TCDD介导的胚胎毒性和血清激素改变的群体剂量反应曲线的影响； (2) 评估人类个体差异对 TCDD 介导的 B 细胞 IgM 分泌抑制的群体剂量反应曲线的影响； (3) 识别和表征与 TCDD 介导的胚胎毒性的菌株间差异相关的基因和途径，以了解其作用模式。将构建 TCDD 介导的胚胎毒性和 B 细胞抑制的计算模型，并用于了解系统在低环境相关剂量下的行为。通过这些具体目标，将在两个不同物种（小鼠和人类）的多个非癌症终点（早期胚胎毒性、类固醇激素改变和 B 细胞免疫抑制）中生成大量科学数据和分析，并使用体内和体外模型来评估 NRC 报告的假设。