SUSCEPTIBILITY DETERMINANTS FOR PHOTOCARCINOGENESIS

光致癌的易感性决定因素

• 批准号: 3456883
• 负责人: PAUL T STRICKLAND
• 金额: $ 9.08万
• 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/3456883
• 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; 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，每个人在他们的 对皮肤癌的易感性以及其他疾病的易感性 器官。这个项目的目标是了解分子 与确定易感性有关的机制 光致癌。将按顺序使用小鼠皮肤模型 利用各种鼠种和品系 记录的身体易感性以及 化学皮肤癌。该项目的总体主题是 为了阐明导致某些小鼠感染或感染的机制 股票对光致癌高度敏感，以及其他 相对有抵抗力。这两个主要领域是 研究内容包括：1)细胞增殖的分子调控和 小鼠皮肤的分化；2)基因毒性的修复 来自小鼠基因组的摄影产物。 对表皮细胞生长的调节将在 小鼠皮肤外植体器官培养的体外应用 不损害组织的实验技术 建筑。正常和受扰的器官培养(UV- 辐照的)表皮组织将被用来检查该规则 外源激素对表皮增殖和分化的影响 培养基中的生长因子/调节剂。 修复小鼠基因组中的DNA光产物将是 调查以确定优先(过度活跃)区域 修复和测量组织中涉及的特定基因的修复 再生和肿瘤性转化。分布情况： DNA限制性内切酶片段中的光产物修复 凝胶电泳法将用单克隆法进行检测 针对DNA照相产物的抗体。修复 特定基因的光产物，特别是癌基因，将是 受到损伤的DNA进行了Southern Blot分析- T4内切酶V和限制性内切酶的特异性切割 消化。 这些实验将提供对我们的 对易感性的分子基础的理解 光致癌。此外，这一知识还可以提供 对1)易感决定因素的性质的洞察 化学致癌；2)组织与组织之间的关系 再生和癌症。