Oxygen-linked Phenol-DNA Adducts

氧连接的苯酚-DNA 加合物

• 批准号: 7110988
• 负责人: SHANA J STURLA
• 金额: $ 14.01万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-08-04 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7110988
• 关键词: DNA damage; adduct; analytical method; catalyst; chemical stability; chemical synthesis; mass spectrometry; method development; nucleic acid structure; nucleoside analog; oligonucleotides; palladium; phenols; purines

DESCRIPTION (provided by applicant): Phenols are ubiquitous components of the human environment. The broad objectives of this research program are to determine the chemical and biochemical processes controlling the balance between their carcinogenic and anticarcinogenic properties. The central hypothesis is that phenolic compounds can form DNA lesions, containing an O-linked aryl group at the C8 position of purine nucleosides, which may contribute to cancer etiology. To develop the chemical tools needed to address these issues, the specific aims of this proposal are: (1) Develop a synthetic approach to phenol-substituted purine nucleoside analogs modified at C8; (2) Synthesize oligonucleotides containing O-linked phenol adducts and determine their stability; and (3) Develop an analytical method for the detection of O-linked phenol adducts and characterize the relationship between phenol activation and adduct formation. The results of this study can be important for evaluating the role of phenols in cancer, developing biomarkers of exposure, generating environmental regulatory guidelines, and establishing concepts important for phenol-based chemoprevention. The candidate will become (July, 2004) an assistant professor of Medicinal Chemistry at the University of Minnesota with an appointment in the Cancer Center. She holds a Ph.D. in Chemistry from MIT, where her research focused on organic synthesis. As an American Cancer Society postdoctoral fellow, the focus shifted to carcinogenesis and chemoprevention. The candidate has been presented with diverse opportunities for professional development through participation in collaborative research, supervising students, grant-writing, departmental service, teaching, and scientific conferences. Immediate career goals include transitioning to an independent faculty position and initiating a research program based on the union of synthetic organic chemistry with the study of carcinogenic mechanisms. The long-term career objective is to foster a rigorously active research group investigating initiation of cancer by environmental agents, diagnostic tools for carcinogen exposure, and prevention methods. The research career development plan is a phased program - a mentored period designed to strengthen the candidate's cancer research skills and professional development, and an independent phase to transition the research to the independent laboratory. The research environment presents faculty expertise and major instrumentation ideally suited for the proposed work.

描述（由申请人提供）：酚是人类环境的无处不在的组成部分。 该研究计划的广泛目标是确定控制其致癌和抗癌特性之间平衡的化学和生化过程。 中心假设是酚类化合物可以形成DNA病变，其中含有嘌呤核苷的C8位置的O连接芳基，这可能有助于癌症病因。 为了开发解决这些问题所需的化学工具，该提案的具体目的是：（1）开发一种合成方法，用于在C8时修改的苯酚取代的嘌呤核苷类似物； （2）合成含有O连接苯酚加合物的寡核苷酸并确定其稳定性； （3）开发一种分析方法，用于检测O连锁苯酚加合物并表征苯酚激活与加合物形成之间的关系。 这项研究的结果对于评估苯酚在癌症中的作用，开发暴露的生物标志物，生成环境调节指南以及确定对基于苯酚的化学预防重要的概念很重要。 候选人将成为明尼苏达大学的药物化学助理教授，并在癌症中心任命。 她拥有博士学位。在MIT的化学中，她的研究集中在有机合成上。 作为美国癌症学会博士后研究员，重点转移到了癌变和化学预防上。 通过参与合作研究，监督学生，授予写作，部门服务，教学和科学会议，候选人获得了专业发展的不同机会。 直接的职业目标包括过渡到独立的教师职位，并通过对致癌机制的研究来启动基于合成有机化学结合的研究计划。 长期职业目标是培养一个严格的活跃研究小组，调查环境药物对癌症的启动，致癌物暴露的诊断工具和预防方法。 研究职业发展计划是一个分阶段的计划 - 旨在增强候选人的癌症研究技能和专业发展的指导时期，也是将研究转换为独立实验室的独立阶段。 研究环境介绍了教师专业知识和主要仪器，非常适合拟议的工作。