Biochemical Reaction Network Modeling of PCB Mixtures

PCB 混合物的生化反应网络建模

• 批准号: 6924372
• 负责人: ARTHUR N MAYENO
• 金额: $ 14.06万
• 依托单位: COLORADO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2010-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6924372
• 关键词: biological models; biotransformation; chemical models; chemical structure function; computational biology; computer simulation; cytochrome P450; detoxification; environmental contamination; halobiphenyl /halotriphenyl compound; isozymes; model design /development; molecular dynamics; toxicology

DESCRIPTION (provided by applicant) The candidate, Dr. Arthur Mayeno, is applying for a K25 Mentored Quantitative Research Career Development Award, in hope of achieving his long-term goal of becoming an independent researcher in quantitative and computational modeling of biological systems. After earning a Ph.D. in organic chemistry and working in the pharmaceutical industry for several years as an analytical chemist, he wishes to transition back into academic research and apply his knowledge and experience in chemistry toward biomedical research. Professor Raymond Yang, in the Department of Environmental and Radiological Health Sciences at Colorado State University, has agreed to be his mentor. Both he and the Department are committed to helping Dr. Mayeno achieve his goals by providing guidance, support, and the research environment. Dr. Mayeno has proposed a career development plan tailored to his needs that include coursework, participation at meetings and workshops, training in the responsible conduct of research, limited teaching, and research in a relevant area of computational toxicology. The proposed research centers on modeling the biotransformation of polychlorinated biphenyls (PCBs), a family of 209 related chemicals, which are ubiquitous environmental pollutants. Although it is known that PCBs and their metabolites exert biological and toxic effects on humans and other organisms, the underlying mechanism behind these health effects remains unclear due, in part, to the complexity of the biochemical interactions involved. A successful model should permit the study and simulation of the metabolism of complex PCB mixtures more representative of the true exposure, and more importantly, provide insight into the underlying molecular basis for the toxicology of PCBs. The proposal herein represents just the first step in developing a comprehensive model and will focus on modeling the biotransformation of PCBs by a single relevant cytochrome P450 (CYP) isozyme, CYP1A1. The research will be accomplished via the following specific aims: In specific aim 1, quantitative structure-reactivity correlations (QSRCs) will be determined that correlate the molecular parameters of a PCB with its rate of metabolism and the site(s) of reaction within the PCB molecule. In addition, a database of "reaction rules" describing the reactions catalyzed by CYP1A1 will be developed to represent the biotransformation pathways. In specific aim 2, the QSRCs and reaction rules will be used to create reaction network models for PCB metabolism. Finally, in specific aim 3, the model(s) will be refined and validated.

描述(由申请人提供) 候选人Arthur Mayeno博士正在申请K25导师量化研究职业发展奖，希望实现他成为生物系统定量和计算建模领域的独立研究员的长期目标。在获得有机化学博士学位并在制药行业担任分析化学家几年后，他希望重新过渡到学术研究领域，并将他在化学方面的知识和经验应用于生物医学研究。科罗拉多州立大学环境与放射健康科学系的雷蒙德·杨教授已同意担任他的导师。他和国防部都致力于通过提供指导、支持和研究环境来帮助马耶诺博士实现他的目标。马耶诺博士提出了一项针对他的需求量身定做的职业发展计划，其中包括课程作业、参加会议和研讨会、负责任地进行研究的培训、有限的教学以及计算毒理学相关领域的研究。拟议的研究重点是对多氯联苯(PCbs)的生物转化进行建模，多氯联苯是一类209种相关化学物质，是普遍存在的环境污染物。尽管已知多氯联苯及其代谢物对人类和其他生物体产生生物和毒性影响，但这些健康影响背后的潜在机制仍不清楚，部分原因是所涉及的生化相互作用的复杂性。一个成功的模型应该允许研究和模拟复杂的多氯联苯混合物的代谢，更能代表真实的暴露，更重要的是，为多氯联苯的毒理学提供潜在的分子基础。这里的提议只代表了开发一个全面模型的第一步，并将专注于通过单个相关的细胞色素P450(CYP)同工酶--CYP1A1来模拟多氯联苯的生物转化。这项研究将通过以下具体目标完成：在具体目标1中，将确定定量结构-反应性相关性(QSRCs)，将多氯联苯的分子参数与其新陈代谢速度和多氯联苯分子中的反应位置(S)相关联。此外，还将开发一个“反应规则”数据库，描述由CYP1A1催化的反应，以代表生物转化途径。在具体目标2中，将使用QSRCs和反应规则来创建多氯联苯代谢的反应网络模型。最后，在具体目标3中，对模型(S)进行细化和验证。