CELLULAR & MOLECULAR BASIS FOR BASAL CELL NEVUS SYNDROME

描述：(改编自申请人的摘要)长期 这项建议的目的是研究细胞和分子 罹患皮肤癌的遗传易感性基础 BCNS.然而，目前的提案仅涉及蜂窝方面， 虽然未来对分子方面的研究是可以预见的。BCNS是一种 常染色体显性遗传病 易患多发性基底细胞痣和基底细胞癌。 初步研究表明，BCNS的皮肤成纤维细胞 个体对UV-B/A(280-400 nm)的杀戮过敏，但不敏感 UV-C(254 Nm)辐射，与正常皮肤成纤维细胞比较 个人。然而，UV-B/A诱导的嘧啶切除修复 二聚体在BCNS和正常人皮肤成纤维细胞中相似。这些 结果表明，BCNS皮肤成纤维细胞对 UV-B/A辐射致死不是由于切除修复中的缺陷 但这是由于某些其他修复机制的缺陷 涉及嘧啶二聚体或其他尚未鉴定的 摄影产品。太阳光中存在的UV-B辐射是已知的 对大多数人类皮肤癌的诱发负有责任，共同 根据研究人员的观察，BCNS细胞对 被UV-B/A辐射杀死，支持了这样的假设 对UV-B/A辐射的杀戮过敏与 和BCNS患者对日光诱导的遗传易感性 皮肤癌。 这项建议的具体目的是：(1)测量灵敏度(在 BCNS和正常人皮肤成纤维细胞和表皮细胞的存活条件 细胞至宽带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 紫外线对BCNS皮肤成纤维细胞和表皮细胞DNA损伤的影响 和普通人。细胞存活率将通过集落形成进行检测 才能。嘧啶二聚体的修复、(6-4)光产物和 DNA的单链断裂将在不同的时间进行测量 紫外线后恢复阶段。申请者表示，一个重要的方面 这项修订后的应用是确定表皮细胞是否 BCNS患者也表现出对紫外线的敏感性增加和类似的修复 缺如(S)为皮肤成纤维细胞。使用表皮细胞的实验，他们 坚持认为是高度相关的，因为大多数发生在BCNS的皮肤癌 患者起源于表皮。针对这些问题的研究可能 导致识别出与以下各项相关的一些缺陷 BCNS患者皮肤癌的发病机制。

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.