Chemoprevention of benzo(a)pyrene-induced colon carcinogenesis

苯并（a）芘诱导的结肠癌的化学预防

• 批准号: 8390221
• 负责人: Ashley Corrin Huderson
• 金额: $ 2.56万
• 依托单位: MEHARRY MEDICAL COLLEGE
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8390221
• 关键词: Adult; Animals; Area; Aromatic Polycyclic Hydrocarbons; Benzo(a)pyrene; Berry; Biological Availability; Breast; CYP1A1 gene; Cancer Etiology; Characteristics; Chemicals; Chemoprevention; Colon; Colon Carcinoma; Colonic Neoplasms; Colorectal; Colorectal Cancer; Consumption; Cytochrome P450; DNA; DNA Damage; Detoxification Process; Development; Diet; Dose; Environment; Environmental Carcinogens; Environmental Exposure; Enzymes; Epidemiology; Equilibrium; Esophagus; Etiology; Evaluation; Event; Family; Fellowship; Food; Glutathione S-Transferase; Goals; Grapes; Health; Human; Intervention; Journals; Kinetics; Label; Life Style; Liver; Longevity; Lung; Malignant Neoplasms; Measures; Mediating; Mentors; Metabolic Biotransformation; Metabolic Pathway; Mus; Neoplasm Metastasis; Organ; Peanuts - dietary; Peer Review; Phytochemical; Plants; Preventive; Publishing; Quality of life; Rectum; Research; Research Activity; Resources; Resveratrol; Risk; Role; Scientist; Staging; Stomach; Surveys; Techniques; Testing; Therapeutic Agents; Thin Layer Chromatography; Time; Tissues; Toxic Environmental Substances; Training; Transgenic Mice; Visit; Work; adduct; adenoma; base; benzo(a)pyrene-DNA adduct; cancer therapy; carcinogenesis; career development; chemical group; chemotherapeutic agent; colon carcinogenesis; efficacy testing; environmental chemical; exposed human population; interest; jejunum; male; meetings; member; mouse model; novel; pre-doctoral; prevent; prophylactic; research study; toxicant

DESCRIPTION (provided by applicant): Benzo(a)pyrene (BaP), an ubiquitous environmental carcinogen, is a member of the polycyclic aromatic hydrocarbon (PAH) family of compounds. Our preliminary studies have shown that BaP causes colon cancer. Our studies have also shown that administration of resveratrol (RVT) to BaP-treated ApcMn mouse reduces the development of adenomas in colon. Our proposed studies will test the hypothesis that RVT modulates BaP - induced colon carcinogenesis through cytochrome P450 (CYP)-mediated metabolic pathways. These studies, in the context of human exposure, could have a significant effect on the quality of life by reducing the onset of colorectal cancer. Since most colorectal cancers are caused by diet, which is contaminated by toxicants, environmental exposure is a likely factor in initiating or accelerating sporadic colorectal cancer cases. We will test our hypotheses in adult male transgenic mice with the following specific aims: 1. Determine whether RVT exposure simultaneously, or prior-BaP treatment alters its own bioavailability, bioavailability of BaP, the expression and activities of BaP biotransformation enzymes, metabolite profiles of RVT, and BaP in ApcMn mice; and 2. Evaluate whether RVT exposure simultaneously with, or prior- BaP treatment modulates BaP- DNA adduct concentrations and persistence. This project will provide new and interesting information with regard to the contribution of phytochemical such as RVT towards delaying or preventing the development of colorectal carcinogenesis. In addition to dissertation research, the goals of this fellowship application are to provide the intellectual environment and resources necessary for the applicant to enrich herself in various techniques and approaches in her chosen area of research. To meet these objectives, we propose a training plan that incorporates: 1) Completion of didactic course work; 2) Mentored research activity; 3) Active participation & presentation in meetings, seminars and journal clubs; 4) Interaction with visiting scientists; 5) Periodic evaluation of applicant's research progress; 6) Publishing research findings in peer-reviewed journals; and 7) Participation in career development activities. It is expected that by the end of the training period, the applicant will be creative and successful in her chosen research endeavor and contribute to the diversity of the research workforce, a goal of the Ruth L. Kirschstein predoctoral fellowship. Relevance of this project to human health In U.S alone, every year 56,000 die of colorectal cancer (CRC); consumption of fatty foods rich in BaP was implicated as a possible causative factor. We plan to study the progression of CRC, using a mouse model that mirrors the human CRC scenario. We also propose to use RVT, a component of grapes and berries against CRC. Our findings will be of use to test the efficacy of other plant-based compounds to prevent the development of cancer, and extend the lifespan of people.

描述（由申请人提供）：苯并（a）芘（BaP）是一种普遍存在的环境致癌物，是多环芳烃（PAH）化合物家族的成员。我们的初步研究表明 BaP 会导致结肠癌。我们的研究还表明，给 BaP 处理的 ApcMn 小鼠注射白藜芦醇 (RVT) 可减少结肠腺瘤的发展。我们提出的研究将检验 RVT 通过细胞色素 P450 (CYP) 介导的代谢途径调节 BaP 诱导的结肠癌发生的假设。这些研究在人类暴露的背景下，可能通过减少结直肠癌的发病率对生活质量产生重大影响。由于大多数结直肠癌是由受有毒物质污染的饮食引起的，因此环境暴露可能是引发或加速散发性结直肠癌病例的一个因素。我们将在成年雄性转基因小鼠中测试我们的假设，其具体目标如下： 1. 确定 RVT 同时暴露或先于 BaP 治疗是否会改变 ApcMn 小鼠中其自身的生物利用度、BaP 的生物利用度、BaP 生物转化酶的表达和活性、RVT 的代谢谱和 BaP； 2.评估RVT暴露与BaP治疗同时或之前是否调节BaP-DNA加合物浓度和持久性。该项目将提供有关 RVT 等植物化学物质对延缓或预防结直肠癌发生发展的贡献的新的有趣信息。除了论文研究之外，该奖学金申请的目标是为申请人提供必要的智力环境和资源，以丰富其所选研究领域的各种技术和方法。为了实现这些目标，我们提出了一个培训计划，其中包括： 1) 完成教学课程； 2）指导研究活动； 3) 积极参与会议、研讨会和期刊俱乐部并发表演讲； 4）与访问科学家的互动； 5）定期评估申请人的研究进展； 6）在同行评审期刊上发表研究成果； 7) 参与职业发展活动。预计在培训期结束时，申请人将在她所选择的研究工作中发挥创造力并取得成功，并为研究人员的多样性做出贡献，这是露丝·L·基尔施斯坦博士前奖学金的目标。该项目与人类健康的相关性 仅在美国，每年就有 56,000 人死于结直肠癌 (CRC)；食用富含 BaP 的脂肪食物可能是一个致病因素。我们计划使用反映人类结直肠癌情况的小鼠模型来研究结直肠癌的进展。我们还建议使用葡萄和浆果中的 RVT 成分来对抗 CRC。我们的研究结果将用于测试其他植物化合物预防癌症发展和延长人类寿命的功效。