CELLULAR & MOLECULAR BASIS FOR BASAL CELL NEVUS SYNDROME

蜂窝网络

• 批准号: 3195632
• 负责人: HONNAVARA N. ANANTHASWAMY
• 金额: $ 9.46万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-07-09 至 1993-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3195632
• 关键词: 6 thioguanine; animal old age; athymic mouse; autosomal dominant trait; basal cell carcinoma; cell biology; dimer; disease /disorder proneness /risk; fibroblasts; human subject; light adverse effect; molecular biology; nevus; nonvisual photosensitivity; ouabain; preneoplastic state; pyrimidines; skin neoplasms; solar radiation; ultraviolet radiation

DESCRIPTION: (Adapted from the applicant's abstract) The long-term objective of this proposal is to investigate the cellular and molecular basis for the genetic predisposition to skin cancer of individuals with BCNS. However, the current proposal deals solely with cellular aspects, although future studies on molecular aspects are anticipated. BCNS is an autosomal dominant genetic disorder in which the afflicted individuals are predisposed to multiple basal cell nevi and basal cell carcinomas. Preliminary studies have indicated that skin fibroblasts from BCNS individuals are hypersensitive to killing by UV-B/A (280-400 nm), but not UV-C (254 nm) radiation, compared to skin fibroblasts from normal individuals. However, the excision repair of UV-B/A-induced pyrimidine dimers was similar in BCNS and normal human skin fibroblasts. These results suggest that the increased sensitivity of BCNS skin fibroblasts to killing by UV-B/A radiation is not due to a defect in the excision repair of pyrimidine dimers, but due to a defect in some other repair mechanism involving either pyrimidine dimers or other, as yet, unidentified photoproducts. The fact that UV-B radiation present in sunlight is known to be responsible for the induction of most human skin cancers, together with the investigators' observation that BCNS cells are hypersensitive to killing by UV-B/A radiation, lend credence to the hypothesis that there may be an association between hypersensitivity to killing by UV-B/A radiation and genetic predisposition of individuals with BCNS to sunlight-induced skin cancers. The specific aims of this proposal are: (1) To measure the sensitivity (in terms of survival) of BCNS and normal human skin fibroblasts and epidermal cells to broad-band UV-B/A, UV-A, and monochromatic (297 nm, 302 nm, 313 nm, 334 nm, or 365 nm) radiations; and (2) to examine the repair kinetics of UV-induced DNA damage in skin fibroblasts and epidermal cells from BCNS and normal individuals. Cell survival will be assayed by colony forming ability. The repair of pyrimidine dimers, (6-4) photoproducts and single-strand breaks in the DNA will be measured at various times during the post-UV recovery phase. The applicants state that an important aspect of this revised application is to determine whether the epidermal cells from BCNS patients also exhibit increased UV sensitivity and similar repair defect(s) as skin fibroblasts. The experiments using epidermal cells, they insist, are highly relevant because most skin cancers that arise in BCNS patients are epidermal in origin. Studies addressing these questions may lead to the identification of some of the defects that are associated with the pathogenesis of skin cancer in BCNS patients.

描述：（改编自申请人的摘要）长期 本提案的目的是研究细胞和分子 患有皮肤癌的人患皮肤癌遗传易感性的基础 BCNS。 然而，当前的提议仅涉及蜂窝方面， 尽管对分子方面的未来研究是可预期的。 BCNS是一个 常染色体显性遗传疾病，其中患病个体是 易患多发性基底细胞痣和基底细胞癌。 初步研究表明，来自BCNS的皮肤成纤维细胞 个体对UV-B/A（280-400 nm）的杀伤过敏，但对 UV-C（254 nm）辐射，与正常皮肤成纤维细胞相比 个体 然而，UV-B/A诱导的嘧啶的切除修复 BCNS和正常人皮肤成纤维细胞中的二聚体相似。 这些 结果表明，BCNS皮肤成纤维细胞对 UV-B/A辐射的杀伤不是由于切除修复的缺陷 嘧啶二聚体，但由于其他一些修复机制的缺陷， 涉及嘧啶二聚体或其他尚未确定的 照片产品 太阳光中的UV-B辐射是已知的 与大多数人类皮肤癌的诱发有关， 研究人员观察到BCNS细胞对 紫外线B/A辐射的杀伤，使人们相信， 对UV-B/A辐射杀伤的超敏反应 和遗传易感性的个人与BCNS阳光诱导 皮肤癌 本建议的具体目的是：（1）测量敏感性（在 BCNS和正常人皮肤成纤维细胞和表皮细胞的存活率 细胞的宽带UV-B/A，UV-A，和单色（297 nm，302 nm，313 nm、334 nm或365 nm）辐射;以及（2）检查修复动力学 紫外线诱导的皮肤成纤维细胞和表皮细胞的DNA损伤 和正常的个体。 将通过集落形成来测定细胞存活率 能力 嘧啶二聚体、（6-4）光产物和 DNA中的单链断裂将在不同的时间测量， 紫外线后的恢复阶段。 申请人说，一个重要的方面是， 是为了确定表皮细胞是否 从BCNS患者也表现出增加的紫外线敏感性和类似的修复 皮肤成纤维细胞等缺陷。 使用表皮细胞的实验， 因为大多数皮肤癌发生在BCNS， 患者起源于表皮。 针对这些问题的研究可 导致识别出与以下方面相关的一些缺陷： BCNS患者皮肤癌的发病机制。