Chemoprevention of benzo(a)pyrene-induced colon carcinogenesis

说明(申请人提供)：苯并(A)芘(BaP)是一种普遍存在的环境致癌物质，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，白藜芦醇(RVT)给BaP治疗的ApcMn小鼠减少了结肠腺瘤的发展。我们建议的研究将验证RVT通过细胞色素P450(CYP)介导的代谢途径调控BaP诱导的结肠癌发生的假设。在人类暴露的背景下，这些研究可能会通过减少结直肠癌的发病而对生活质量产生重大影响。由于大多数结直肠癌是由饮食引起的，而饮食受到毒物的污染，环境暴露是引发或加速零星结直肠癌病例的一个可能因素。我们将在成年雄性转基因小鼠中验证我们的假设，具体目的如下：1.确定RVT同时暴露或先前的BaP处理是否改变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和BaP的代谢物分布；以及2.评估RVT暴露与或先前的BaP处理是否调节BaP-DNA加合物的浓度和持久性。该项目将提供有关植物化学物质(如RVT)对延缓或预防结直肠癌发生的贡献的新的和有趣的信息。除了论文研究，该奖学金申请的目标是为申请者提供必要的智力环境和资源，使其在所选研究领域的各种技术和方法上充实自己。为了达到这些目标，我们提出了一项培训计划，其中包括：1)完成教学课程工作；2)指导研究活动；3)积极参与和在会议、研讨会和期刊俱乐部中陈述；4)与来访的科学家互动；5)定期评估申请者的研究进展；6)在同行评议的期刊上发表研究结果；以及7)参与职业发展活动。预计在培训结束时，申请者将在她所选择的研究努力中具有创造性和成功，并为研究人员的多样性做出贡献，这是Ruth L.Kirschstein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的高脂肪食物被认为是可能的致病因素。我们计划使用一个小鼠模型来研究CRC的进展，该模型反映了人类CRC的场景。我们还建议使用RVT，葡萄和浆果的一种成分来对抗结直肠癌。我们的发现将用于测试其他植物性化合物预防癌症发展和延长人类寿命的有效性。

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.