Research Support Core A: Computational Modeling of Mammalian Biomolecular

研究支持核心 A：哺乳动物生物分子的计算模型

• 批准号: 9257391
• 负责人: Rory Clement Bards Conolly
• 金额: $ 44.15万
• 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
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/9257391
• 关键词: AHR gene; Agonist; Antibodies; Antigens; Aryl Hydrocarbon Receptor; B cell differentiation; B-Cell Activation; B-Lymphocytes; Bioenergetics; Biological; Biological Process; CD40 Ligand; Chemicals; Choline; Communities; Complex; Computer Simulation; Development; Developmental Process; Dioxins; Dose; Education; Embryo; Endocrine; Environmental Pollution; Exposure to; Fatty Liver; Funding; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genetic Transcription; Goals; Grant; Health; Health Sciences; Hepatic; Hepatotoxicity; Homeostasis; Human; Immune; Immunosuppression; Impairment; Individual; Influentials; Institutes; Interdisciplinary Study; Investigation; Kinetics; Laboratories; Laboratory Study; Ligands; Link; Liver; Metabolism; Michigan; Mitochondria; Modeling; Mouse Strains; Mus; Oocytes; Organ; Outcome; Pathway interactions; Physiological; Plasma Cells; Play; Population; Pregnancy; Process; Production; Program Research Project Grants; Publishing; Reporting; Research; Research Personnel; Research Project Grants; Research Project Summaries; Research Support; Risk; Risk Assessment; Role; Scientist; Shapes; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Strategic Planning; Structure; Superfund; Systems Biology; Time; Tissues; Toxic effect; Toxicity Tests; Toxicology; Training; United States Environmental Protection Agency; United States National Academy of Sciences; Universities; aryl hydrocarbon receptor ligand; base; biological systems; collaborative approach; computational toxicology; computerized tools; cytokine; design; differentiated B cell; experimental study; immunotoxicity; implantation; improved; lipid metabolism; lipid transport; mathematical model; microbial; natural Blastocyst Implantation; pharmacokinetic model; plasma cell differentiation; programs; response; success

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.

项目摘要（见说明）：研究支持核心A（计算核心）将开发由环境污染物2，3，7，8-四氯二苯并-p-二恶英（TCDD）和相关化合物通过芳烃受体（AhR）作用干扰的毒性途径的数学模型，以支持研究项目1，2，3和4。拟议模型的结构将以适合项目中追求的毒理学终点的详细程度进行，包括免疫毒性、胚胎毒性和生物能量破坏。这些模型代表正在研究的生物系统的功能及其受AhR配体干扰的工作假设，将包含实验验证良好的组件和相互作用，以及拟议的合作研究的重点是更试探性的。多学科合作的潜力体现在我们的成功，在最后一个资助期，协调的建模和实验研究已经导致了很大程度上提高了对TCDD如何抑制B淋巴细胞分化，通过干扰一个转录因子基因网络和随机基因表达如何影响剂量反应曲线的形状的理解。这些发现都不可能仅仅通过实验室实验或计算模型来实现。目前建议的一个基本特点是继续这种协调实验室研究与计算模型开发的方法，只是更广泛。具体目标1将实施一个关键调节基序模型，用于通过多种细胞因子和抗原激活原代人类B细胞，并通过TCDD破坏激活过程（支持项目1和2）。在具体目标2下，将开发生物能量学的多器官模型，目的是更好地了解四氯二苯并对二恶英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）。在具体目标3下，我们将通过开发小鼠早期妊娠的计算模型来支持项目2，以研究TCDD抑制胚胎植入的机制并研究剂量反应。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人员和一般的超级基金研究社区。