Telomere-Mediated Protective Responses in Skin

端粒介导的皮肤保护反应

• 批准号: 7015064
• 负责人: BARBARA A GILCHREST
• 金额: $ 35.58万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-08 至 2008-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7015064
• 关键词: DNA damage; DNA repair; RNA interference; athymic mouse; basosquamous cell carcinoma; biological signal transduction; chemical carcinogen; chemical carcinogenesis; clinical research; cytoprotection; fibroblasts; human tissue; keratinocyte; melanocyte; melanoma; molecular pathology; northern blottings; oligonucleotides; radiation carcinogenesis; skin neoplasms; squamous cell carcinoma; telomere; terminal nick end labeling; tissue /cell culture; ultraviolet radiation; western blottings

DESCRIPTION (provided by applicant): As the environmental interface, skin is subject to damage from many agents including ultraviolet (UV) irradiation, reactive oxygen species (ROS), and chemical carcinogens. DNA is perhaps the most critical target of such damage, and DNA mutations are chiefly responsible for the more than one million skin cancers annually in the U.S. Nucleotide excision repair and other constitutive mechanisms for detecting and repairing DNA damage have been extensively studied, but recent work demonstrates that mammalian cells also have an inducible capacity triggered by an initial DNA insult that evolves over several days and protects against subsequent damage. This inducible repair capacity, best demonstrated in skin, appears to be part of a multifaceted response also involving adaptive differentiation and apoptosis or proliferative senescence of cells at high risk for malignant conversion. We have shown that DNA oligonucleotides homologous to the telomere 3' overhang (T-oligos) induce the same protective responses in the absence of initial DNA damage, via p53 and p16/pRb signaling pathways. We hypothesize that exposure of the telomere 3' I-I'AGGG tandem repeat sequence, known to occur as a result of telomere disruption, also occurs after acute DNA damage or during aging and initiates signaling for protective anti-cancer responses. We further hypothesize that T-oligos mimic this physiologic signal. We propose to delineate the signaling pathways and biologic consequences of these protective responses in human keratinocytes, fibroblasts, and melanocytes, seeking subtle differences among them in activation of the p53 versus p16/pRb pathways that might explain the different susceptibilities and patterns of malignant conversion for these cell types. Using validated mouse models of the three major malignancies in human skin (basal cell carcinoma, squamous cell carcinoma, and melanoma), we will also test the hypothesis that pretreatment with T-oligos reduces the risk of malignancy after UV irradiation or chemical carcinogen exposure. Results from the proposed in vitro and in vivo studies should greatly enhance our understanding of telomere-based protective responses induced in mammalian cells and skin by acute DNA damage or multiple rounds of cell division. The studies will also explore the possible therapeutic potential of T-oligos that comparably induce these responses in the absence of actual DNA damage or telomere disruption.

描述（由申请人提供）： 作为环境界面，皮肤容易受到多种因素的损害，包括紫外线 (UV) 照射、活性氧 (ROS) 和化学致癌物质。 DNA 可能是此类损伤最关键的目标，而 DNA 突变是美国每年超过一百万例皮肤癌的主要原因。核苷酸切除修复和其他检测和修复 DNA 损伤的构成机制已得到广泛研究，但最近的工作证明哺乳动物细胞还具有由最初的 DNA 损伤触发的诱导能力，这种能力会在几天内进化并防止随后的损伤。这种诱导修复能力在皮肤中得到了最好的证明，似乎是多方面反应的一部分，还涉及恶性转化高风险细胞的适应性分化和细胞凋亡或增殖性衰老。我们已经证明，与端粒 3' 突出端同源的 DNA 寡核苷酸（T-oligos）在没有初始 DNA 损伤的情况下，通过 p53 和 p16/pRb 信号通路诱导相同的保护反应。我们假设，端粒 3' I-I'AGGG 串联重复序列的暴露（已知因端粒破坏而发生）也会在急性 DNA 损伤后或衰老过程中发生，并启动保护性抗癌反应的信号传导。我们进一步假设 T-oligos 模仿了这种生理信号。我们建议描绘人类角质形成细胞、成纤维细胞和黑素细胞中这些保护性反应的信号传导途径和生物学后果，寻找它们之间在 p53 与 p16/pRb 途径激活方面的细微差异，这可能解释不同的敏感性和恶性转化模式。这些细胞类型。使用经过验证的人类皮肤三种主要恶性肿瘤（基底细胞癌、鳞状细胞癌和黑色素瘤）的小鼠模型，我们还将测试以下假设：T-oligos 预处理可降低紫外线照射或化学致癌物暴露后患恶性肿瘤的风险。拟议的体外和体内研究结果将大大增强我们对急性 DNA 损伤或多轮细胞分裂在哺乳动物细胞和皮肤中诱导的基于端粒的保护反应的理解。这些研究还将探索 T-oligos 的可能治疗潜力，在没有实际 DNA 损伤或端粒破坏的情况下，T-oligos 可以类似地诱导这些反应。