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

基本信息

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
项目类别：
财政年份：
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

项目摘要

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（请参阅说明）：研究支持核心A（计算核心）将开发毒性途径的数学模型，这些模型受环境污染物的影响2,3,7,8-甲基二苯并二苯甲酸-P-二氧蛋白（TCDD）和相关化合物通过芳基水合物受体（AHR）在研究中的模型和3层的模型1、3，以及4.3 and 4，and 2 cons and 2，4适用于项目中毒理学终点的细节，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功能及其对AHR配体扰动的功能的工作假设，这些模型将包含成分和相互作用，这些组件和相互作用是实验性良好的效果以及更具试探性的组件和相互作用，这些组件和相互作用是拟议协作研究的重点。我们在上一个融资期的成功来说明了多学科合作的潜力，在该期间，协调的建模和实验研究已经使人们对TCDD如何通过干扰Bisesable Gene网络以及随机基因表达影响剂量反应依次的形状来抑制B淋巴细胞的分化有很大的了解。这些发现都不能仅通过实验室实验或计算建模做出。当前建议的一个基本特征是继续这种方法来协调实验室研究与计算模型的开发，只有更广泛的方式。具体目标1将实施一个关键调节基序模型，以通过多种细胞因子和抗原激活原代人B细胞，以及TCDD（支持项目1和2）对激活过程的破坏。在特定目标下，将开发出一种多晶型生物能学模型，目的是更好地了解TCDD肝肝稳态如何导致脂肪肝，胆碱代谢的改变以及线粒体功能的破坏（在支持项目3和4中）。在特定目标3下，我们将通过开发早期小鼠怀孕的计算模型来支持项目2，以研究TCDD抑制胚胎植入和研究剂量反应的机制。最后，在与培训核心的协调下，特定的目标4将为研究项目受训者和研究人员以及一般超级基金研究社区提供计算毒理学课程。