Biochemical Reaction Network Modeling of PCB Mixtures

描述（由申请人提供） 候选人亚瑟Mayeno博士正在申请K25指导定量研究职业发展奖，希望实现他的长期目标，成为生物系统定量和计算建模的独立研究人员。获得博士学位后，他在有机化学方面有丰富的经验，并在制药行业担任分析化学家多年，他希望重新过渡到学术研究，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Raymond Yang教授已同意成为他的导师。 他和该部门都致力于帮助博士Mayeno通过提供指导，支持和研究环境来实现他的目标。Mayeno提出了一个职业发展计划，根据他的需要，包括课程，参加会议和研讨会，在负责任的研究行为，有限的教学，并在计算毒理学的相关领域的研究培训。拟议的研究中心对多氯联苯（PCB）的生物转化进行建模，PCB是一个由209种相关化学物质组成的家族，是普遍存在的环境污染物。虽然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基本机制仍不清楚，部分原因是所涉及的生物化学相互作用的复杂性。 一个成功的模型应允许研究和模拟复杂的多氯联苯混合物的代谢更代表的真实的接触，更重要的是，提供深入了解的潜在的多氯联苯的毒理学的分子基础。本文的建议只是第一步，在开发一个全面的模型，并将重点放在模拟生物转化的多氯联苯的一个单一的相关细胞色素P450（CYP 1A 1）同工酶。该研究将通过以下具体目标来完成：在具体目标1中，将确定定量结构-反应性相关性（QSRC），该相关性将PCB的分子参数与其代谢速率和PCB分子内的反应位点相关联。 此外，还将开发描述CYP 1A 1催化反应的“反应规则”数据库，以代表生物转化途径。在具体目标2中，将使用QSRC和反应规则来创建PCB代谢的反应网络模型。 最后，在具体目标3中，将对模型进行细化和验证。

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.