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: 8564249
• 负责人: Rory Clement Bards Conolly
• 金额: $ 27.61万
• 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/8564249
• 关键词: AHR gene; Accounting; Agonist; Antibodies; Antigens; Aryl Hydrocarbon Receptor; B cell differentiation; B-Cell Activation; B-Lymphocytes; Bioenergetics; 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; Goals; Grant; Health; Health Sciences; Hepatic; Hepatotoxicity; Homeostasis; Human; Immune; Immunosuppression; Individual; Influentials; Institutes; Instruction; Interdisciplinary Study; Investigation; Kinetics; Laboratories; Laboratory Study; Ligands; Link; Liver; Metabolism; Michigan; Mitochondria; Modeling; Mouse Strains; Mus; Oocytes; Organ; Organ Model; Outcome; Pathway interactions; Plasma Cells; Play; Population; Pregnancy; Process; Production; Program Research Project Grants; Publishing; Receptor Signaling; Reporting; Research; Research Personnel; Research Project Grants; 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; Work; aryl hydrocarbon receptor ligand; base; biological systems; computerized tools; cytokine; design; immunotoxicity; implantation; improved; lipid metabolism; lipid transport; mathematical model; microbial; natural Blastocyst Implantation; pharmacokinetic model; plasma cell differentiation; programs; research study; 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（参见说明）：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) 和相关化合物干扰的毒性途径的数学模型，这些化合物通过芳基碳氢化合物受体（AhR）以支持研究项目 1、2、3 和 4。所提出的模型将按照适合于研究项目中所追求的毒理学终点的详细程度进行构建。项目包括免疫毒性、胚胎毒性和生物能破坏。这些模型代表了有关正在研究的生物系统的功能及其受到 AhR 配体的扰动的工作假设，将包含经过实验充分验证的成分和相互作用，以及作为拟议合作研究重点的更具尝试性的成分和相互作用。我们在上一个资助期的成功证明了多学科合作的潜力，协调的建模和实验研究使人们更好地了解 TCDD 如何通过干扰双稳态基因网络来抑制 B 淋巴细胞分化，以及随机基因表达如何影响形状剂量反应曲线。这些发现不可能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开发的方法，只是更广泛地进行。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，将开发生物能学的多器官模型，目的是更好地了解 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 抑制胚胎着床的机制并研究剂量反应。最后，在与培训核心的协调下，Specific Aim 4 将为研究项目学员和研究人员以及整个超级基金研究社区提供计算毒理学课程。