MOLECULAR CHEMOPREVENTION MECHANISMS OF TEA POLYPHENOLS

茶多酚的分子化学预防机制

• 批准号: 6378120
• 负责人: STEVEN P STRATTON
• 金额: $ 11.01万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-08-01 至 2005-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6378120
• 关键词: RNase protection assay; antioxidants; carcinogenesis inhibitor; cell cycle; cell line; chemoprevention; confocal scanning microscopy; flavonoids; flow cytometry; free radical oxygen; gas chromatography mass spectrometry; keratinocyte; laboratory mouse; lipid peroxides; radiation protection; skin neoplasms; tea; topical drug application; transcription factor; ultraviolet radiation

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.

描述：（申请人的描述）预防是最有效的方法 降低癌症的发病率、发病率和死亡率。 因此，发展 癌症预防研究中新的研究者势在必行。 史蒂文·斯特拉顿博士是癌症领域的初级研究员 预防;接受过分析化学、毒理学、药理学方面的培训， 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 斯特拉顿博士成长为一名完全独立的研究者。 这 项目将在亚利桑那州癌症中心（国家癌症中心）进行 研究所指定的综合癌症中心，拥有国际化水平 在癌症预防研究领域享有盛誉。 拟议的研究 将在皮肤癌化学预防的支持下进行 亚利桑那大学的计划项目。这个项目将重点关注皮肤 茶多酚衍生物的癌症化学预防机制， 茶花。 绿茶是人们消费最广泛的饮料之一 世界。 许多体内和体外研究表明，多酚 茶叶中存在的化合物可抑制皮肤癌的发生，但其机制 行动仍未知。 理解这一机制对于 使用这些化合物开发化学预防策略。 这个项目 将检验绿茶多酚预防紫外线的假设 通过调节活性氧介导的辐射诱发皮肤癌 正常细胞功能的改变。 活性氧和次级标记物 将利用膜损伤来探索茶多酚的作用 体外使用人类角质形成细胞进行紫外线诱导的皮肤细胞转化 体内小鼠皮肤模型。 该项目的具体目标包括分析 绿茶多酚对：（1）细胞膜脂质过氧化作用 使用新的灵敏且特异的 GC/MS 检测来量化氧化水平 生物分子； (2) 细胞周期进展及细胞周期调控的表达 使用流式细胞术和 RNase 保护技术检测基因； (3) 监管 使用碱性磷酸酶报告系统激活转录因子； (4)相关转录因子的凋亡和易位 原位分子成像技术。 这些标记物水平的变化将 用于建立茶多酚和茶多酚的抗氧化作用之间的联系 对氧化还原敏感的下游事件可能产生直接影响。 整体 该项目的目标是促进学术研究的发展 分子化学预防框架内的癌症预防事业 机械研究和培训。 近期目标包括获得 独立调查所需的科学和技术专业知识 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、测定方法和专业知识 生化过程；分子化学预防的建立 实验室;分子合作研究项目的发展 癌症预防机制；最终，发展 降低癌症发病率和死亡率的化学预防疗法。