MOLECULAR CHEMOPREVENTION MECHANISMS OF TEA POLYPHENOLS

描述：（申请人描述）预防是最有效的方法 降低癌症的发病率、致残率和死亡率。 因此，发展 癌症预防研究的新研究人员是必要的。 史蒂文·P·斯特拉顿博士是癌症领域的初级研究员 预防;在分析化学，毒理学，药理学， 癌症治疗、癌症药物开发和癌症预防 流行病学 该奖项支持的指导培训将促进 斯特拉顿医生成长为完全独立的调查员 这 该项目将在亚利桑那州癌症中心进行，这是一个国家癌症中心。 研究所指定的综合癌症中心，拥有国际 在癌症预防研究方面享有卓越的声誉。 拟议的研究 将在皮肤癌化学预防计划的支持下进行 亚利桑那大学的项目。这个项目将集中在皮肤 使用茶的多酚衍生物的癌症化学预防机制， 茶树。 绿色茶是中国最广泛消费的饮料之一。 世界 许多体内和体外研究表明，多酚类化合物 茶中存在的化合物抑制皮肤致癌作用，尽管 行动仍然未知。 了解这一机制对于 开发使用这些化合物的化学预防策略。 这个项目 将检验绿色茶多酚防止紫外线的假设 通过调节活性氧介导的辐射诱导的皮肤癌发生 正常细胞功能的改变。 活性氧和继发性 膜损伤将被用来探讨茶多酚在 紫外线诱导人皮肤角质形成细胞转化的体外研究 体内小鼠皮肤模型。 该项目的具体目标包括分析 绿色茶多酚对细胞膜脂过氧化的影响 使用新的灵敏度和特异性GC/MS分析来定量氧化的 （2）细胞周期进程和细胞周期调控的表达 基因的流式细胞术和RNA酶保护技术;（3）调节 使用碱性磷酸酶报告系统激活转录因子; （4）细胞凋亡及相关转录因子的转位 原位分子成像技术。 这些标志物水平的变化将 用于建立茶多酚的抗氧化作用与 可能对氧化还原敏感的下游事件产生直接影响。 整体 本项目的目标是促进学术研究的发展 在分子化学预防框架内从事癌症预防工作 机械学习和培训。 近期目标包括获得 独立调查所需的科学和技术专门知识 二级癌症预防机制。 长期职业目标包括 开发氧化还原调节的新方法，测定和专业知识 生物化学过程;分子化学预防的建立 实验室;发展合作研究计划，在分子 癌症预防机制;最终， 减少癌症发病率和死亡率的化学预防疗法。

DESCRIPTION: (Applicant's Description) Prevention is the most efficient way to reduce the incidence, morbidity, Nd mortality of cancer. Thus, development of new investigators in cancer prevention research is imperative. Steven P. Stratton, Ph.D. is a junior investigator in the field of cancer prevention; with training in analytical chemistry, toxicology, pharmacology, cancer therapeutics, cancer drug development, and cancer prevention epidemiology. The mentored training supported by this award will facilitate the development of Dr. Stratton into a fully independent investigator. This project will be conducted at the Arizona Cancer Center, a National Cancer Institute-designated comprehensive cancer center with an international reputation for excellence in cancer prevention research. The proposed studies will be performed under the aegis of the Chemoprevention of Skin Cancer Program Project at the University of Arizona. This project will focus on skin cancer chemoprevention mechanisms with polyphenolic derivatives of tea, Camellia sinensis. Green tea is one of the most widely consumed beverages in the world. Many studies both in vivo and in vitro suggest that polyphenolic compounds present in tea inhibit skin carcinogenesis, though the mechanism of action is still unknown. An understanding of this mechanism is crucial to the development of chemopreventive strategies using these compounds. This project will test the hypothesis that green tea polyphenols prevent UV radiation-induced skin carcinogenesis by modulating reactive oxygen-mediated alterations of normal cell function. Markers of reactive oxygen and secondary membrane damage will be used to explore the role of tea polyphenols in UV-induced skin cell transformation using human keratinocytes in vitro and an in vivo mouse skin model. The specific aims of this project include analyzing the effects of green tea polyphenols on: (1) Cell membrane lipid peroxidation using new sensitive and specific GC/MS assays to quantify levels of oxidized biomolecules; (2) Cell cycle progression and expression of cell cycle control genes using flow cytometry and RNase protection techniques; (3) Regulation of transcription factor activation using an alkaline phosphatase reporter system; and (4) Apoptosis and translocation of relevant transcription factors using in situ molecular imaging techniques. Changes in levels of these markers will be used to establish links between antioxidant effects of tea polyphenols and possible direct effects on redox-sensitive downstream events. The overall goal of this project is to promote the development of an academic research career in cancer prevention within a framework of molecular chemoprevention mechanistic studies and training. Immediate goals include acquiring the scientific and technical expertise necessary for independent investigations of secondary cancer prevention mechanisms. Long-term career goals include development of new methods, assays, and expertise in redox-modulated biochemical processes; establishment of a molecular chemoprevention laboratory; development of collaborative research programs in molecular mechanisms of cancer prevention; and ultimately, development of chemopreventive therapies that reduce cancer morbidity and mortality.