Research Support Core A: Computational Modeling of Mammalian Biomolecular

项目摘要(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。拟议的模型将以适合项目所追求的毒理学终点的详细程度构建，包括免疫毒性、胚胎毒性和生物能量干扰。这些模型代表了关于正在研究的生物系统的功能及其被AhR配体扰动的工作假说，这些模型将包含经过实验验证的组件和相互作用，以及更具试验性的组件和相互作用，这是拟议的合作研究的重点。我们在上一个资助期的成功证明了多学科合作的潜力，在那里，协调的建模和实验研究大大提高了对TCDD如何通过干扰双稳基因网络抑制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形状的理解。这些发现都不可能仅靠实验室实验或计算模型来得出。目前提案的一个基本特点是继续这种协调实验室研究与开发计算模型的方法，只是范围更广。具体目标1将实施一个关键调控基序模型，用于多种细胞因子和抗原激活原代人类B细胞，以及TCDD扰乱激活过程(在支持项目1和2中)。在具体目标2下，将开发生物能量学的多器官模型，目的是更好地了解TCDD如何扰乱肝脏能量平衡，导致脂肪肝、胆碱代谢改变和线粒体功能中断(支持项目3和4)。在具体目标3下，我们将通过开发小鼠妊娠早期的计算模型来支持项目2，以研究TCDD抑制胚胎着床的机制和研究剂量反应。最后，在与培训核心的协调下，特定目标4将向研究项目受训人员和研究人员以及普通超级基金研究社区提供计算毒理学课程。

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.