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.

阳光下的紫外线辐射是皮肤癌的主要原因 在人类中。 但是，个人的差异很大 在其他方面对皮肤癌和癌症的敏感 器官。 该项目的目的是了解分子 确定易感性的机制 光钙局发生。 鼠标皮肤模型将按顺序使用 利用各种鼠标库存和应变 记录了对身体易感性以及 化学皮肤致癌。 该项目的总体主题是 阐明引起某些小鼠菌株或 股票高度容易受到光钙化发生，其他股票 相对抗性。 两个一般区域 研究的是1）细胞增殖的分子调节和 鼠皮的分化和2）修复遗传毒性 来自鼠基因组的光产物。 将研究表皮细胞生长的调节 为了体外使用小鼠皮肤外植体的器官培养物 实验技术没有损害组织 建筑学。 正常和扰动的器官培养（UV- 辐照）表皮组织将用于检查调节 外源性表皮增殖和分化 培养基中的生长因子/调节剂。 修复鼠基因组中DNA光产物的修复 调查以识别优先区域（多动） 修复并测量与组织有关的特定基因的修复 再生和肿瘤转化。 分布 DNA分数的限制性片段的光产物修复 通过凝胶电泳将使用单克隆 DNA光产物特异性的抗体。 维修 特定基因中的光产物，特别是癌基因，将是 通过对受损伤的DNA的Southern印迹分析进行检查 - T4核酸内切酶V和限制酶的特定裂解 消化。 这些实验将为我们的信息提供至关重要的信息 了解分子基础的易感性 光钙局发生。 此外，这些知识可能会提供 洞察1）易感决定因素的性质 化学癌变和2）组织之间的关系 再生和癌症。