Research Support Core A: Computational Modeling of Mammalian Biomolecular

项目概述（见说明）：研究支持核心A（计算核心）将开发受环境污染物2,3,7,8-四氯二苯并对二恶英（TCDD）和通过芳烃受体（AhR）作用的相关化合物干扰的毒性途径的数学模型，以支持研究项目1,2,3和4。拟议的模型将按照项目中所追求的毒理学终点（包括免疫毒性、胚胎毒性和生物能量破坏）的详细程度进行构建。这些模型代表了正在研究的生物系统的功能和AhR配体对它们的扰动的工作假设，这些模型将包含实验上得到充分验证的成分和相互作用，以及更多的试验性成分和相互作用，这些成分和相互作用是拟议合作研究的重点。我们在上一个资助期的成功证明了多学科合作的潜力，其中协调建模和实验研究使人们对TCDD如何通过干扰双稳态基因网络抑制B淋巴细胞分化以及随机基因表达如何影响剂量反应曲线的形状有了更深入的了解。这些发现都不可能仅仅通过实验室实验或计算模型得出。当前提案的一个基本特征是继续这种协调实验室研究与计算模型发展的方法，只是范围更广。具体目标1将实现一个关键调控基序的模型，用于多种细胞因子和抗原激活原代人B细胞，以及TCDD对激活过程的破坏（支持项目1和2）。在Specific Aim 2下，将开发一个多器官生物能量学模型，目的是更好地理解TCDD如何扰乱肝脏能量稳态，导致脂肪肝、胆碱代谢改变和线粒体功能破坏（支持项目3和4）。在Specific Aim 3下，我们将通过建立小鼠早期妊娠的计算模型来研究TCDD抑制胚胎着床的机制并研究剂量反应来支持项目2。最后，与培训核心协调，具体目标4将提供计算毒理学课程研究项目的学员和调查员和一般超级基金研究社区。

PROJECT SUMMARY (See instructions): The Research Support Core A (Computational Core) will develop mathematical models of toxicity pathways perturbed by the environmental contaminant 2,3,7,8-tetrachlorodiobenzo-p-dioxin (TCDD) and related compounds acting via the aryl hydrocarbon receptor (AhR) in support of Research Projects 1, 2, 3, and 4. The proposed models will be structured at a level of detail appropriate to the toxicological endpoints being pursued in the Projects, including immunotoxicity, embryotoxicity and bioenergetic disruption. Representing working hypotheses about the functions of the biological systems being studied and their perturbation by AhR ligands, these models will contain components and interactions that are experimentally well-validated as well as more tentative ones that are the focus of the proposed collaborative research. The potential of multidisciplinary collaborations is exemplified by our success in the last funding period, where coordinated modeling and experimental research has led to much improved understanding of how TCDD suppresses B lymphocyte differentiation through interfering with a bistable gene network and how stochastic gene expression influences the shape of dose response curves. None of these findings could have been made by laboratory experimentation or computational modeling alone. An essential feature of the current proposal is to continue this approach of coordinating laboratory studies with development of computational models, only more extensively. Specific Aim 1 will implement a model of key regulatory motifs for the activation of primary human B cells by multiple cytokines and antigens, and the disruption of the activation processes by TCDD (in supporting Projects 1 and 2). Under Specific Aim 2 a multi-organ model of bioenergetics will be developed, with the goal of better understanding how TCDD perturbs hepatic energy homeostasis, leading to fatty liver, alteration of choline metabolism, and disruption of mitochondrial function (in supporting Projects 3 and 4). Under Specific Aim 3 we will support Project 2 by developing a computational model of early mouse pregnancy to investigate the mechanism by which TCDD suppresses embryonic implantation and study dose responses. Finally, in coordination with the Training Core, Specific Aim 4 will offer computational toxicology courses to Research Project trainees and investigators and the general Superfund Research community.