SUSCEPTIBILITY DETERMINANTS FOR PHOTOCARCINOGENESIS

光致癌的易感性决定因素

• 批准号: 3456886
• 负责人: PAUL T STRICKLAND
• 金额: $ 11.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-04-01 至 1993-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3456886
• 关键词: cell differentiation; chemical carcinogenesis; disease /disorder proneness /risk; endonuclease; genome; laboratory mouse; light adverse effect; monoclonal antibody; neoplasm /cancer genetics; oncogenes; organ culture; preneoplastic state; radiation carcinogenesis; regeneration; skin neoplasms; southern blotting; ultraviolet radiation

Ultraviolet radiation in sunlight is the major cause of skin cancer in humans. However, individuals differ considerably in their susceptibility to cancer of the skin as well as cancer in other organs. The goal of this project is to understand the molecular mechanisms involved in determining susceptibility to photocarcinogenesis. The mouse skin model will be used in order to take advantage of the variety of mouse stocks and strains with documented differences in susceptibility to physical as well as chemical skin carcinogenesis. The overall theme of the project is to elucidate the mechanisms that cause some mouse strains or stocks to be highly susceptible to photocarcinogenesis, and others to be relatively resistant. The two general areas to be investigated are 1) molecular regulation of cell proliferation and differentiation in murine skin, and 2) repair of genotoxic photoproducts from the murine genome. Regulation of cell growth in the epidermis will be investigated in organ cultures of mouse skin explants in order to use in vitro experimental techniques without compromising tissue architecture. Organ cultures of normal and perturbed (UV- irradiated) epidermal tissue will be used to examine the regulation of epidermal proliferation and differentiation by exogenous growth factors/modulators in the culture media. Repair of DNA photoproducts in the murine genome will be investigated to identify regions of preferential (hyperactive) repair and to measure repair in specific genes involved in tissue regeneration and neoplastic transformation. The distribution of photoproduct repair in restriction fragments of DNA fractionated by gel electrophoresis will be examined using monoclonal antibodies specific for DNA photoproducts. Repair of photoproducts in specific genes, particularly oncogenes, will be examined by Southern Blot analysis of DNA subjected to damage- specific cleavage by T4 endonuclease V and restriction enzyme digestion. These experiments will provide information critical to our understanding of the molecular basis for susceptibility to photocarcinogenesis. In addition, this knowledge may provide insights into 1) the nature of susceptibility determinants for chemical carcinogenesis, and 2) the relationship between tissue regeneration and cancer.

阳光中的紫外线辐射是皮肤癌的主要原因 在人类身上。 然而，个人在他们的 对皮肤癌以及其他癌症的易感性 机关 这个项目的目标是了解 参与确定易感性的机制 光致癌作用 将使用小鼠皮肤模型， 利用小鼠种群和品系的多样性， 记录了对物理和化学物质敏感性的差异 化学性皮肤癌 该项目的总体主题是 阐明导致某些小鼠品系或 对光致癌作用高度敏感的种群，以及其他 相对来说是有抵抗力的。 这两个一般领域是 研究了1）细胞增殖的分子调控， 小鼠皮肤中的分化，和2）修复遗传毒性 来自小鼠基因组的光产物。 表皮细胞生长的调节将在 小鼠皮肤外植体的器官培养物，以便在体外使用 不损害组织的实验技术 架构 器官培养正常和扰动（UV- 辐射）表皮组织将用于检查调节 表皮细胞的增殖和分化 生长因子/调节剂。 小鼠基因组中DNA光产物的修复将是 研究以确定优先（过度活跃）区域 修复和测量组织中涉及的特定基因的修复 再生和肿瘤转化。 的分布 分离DNA限制性片段的光产物修复 将使用单克隆抗体进行凝胶电泳检查 DNA光产物特异性抗体。 修复 特定基因中的光产物，特别是癌基因， 通过DNA的Southern印迹分析， 通过T4核酸内切酶V和限制性内切酶特异性切割 消化. 这些实验将为我们提供重要的信息， 了解易感性的分子基础 光致癌作用 此外，这些知识可以提供 1）易感性决定因素的性质， 化学致癌作用，2）组织之间的关系 再生和癌症。