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，皮肤受到许多药物的损害，包括紫外线（UV）辐射，活性氧（ROS）和化学致癌物。 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.这种可诱导的修复能力在皮肤中最好证明，似乎是多方面反应的一部分，涉及适应性分化，凋亡或细胞的增殖性衰老，处于恶性转化的高风险。我们已经表明，通过p53和p16/prb信号通路，在没有初始DNA损伤的情况下，在没有初始DNA损伤的情况下，DNA寡核苷酸与端粒3'悬垂（T-Oligos）同源。我们假设端粒3'I-i'Aggg串联重复序列的暴露（已知是由于端粒破坏而发生的）也发生在急性DNA损伤或衰老期间，并启动了保护性抗癌反应的信号传导。我们进一步假设T-Oligos模仿该生理信号。我们建议描绘人角质形成细胞，成纤维细胞和黑色素细胞中这些保护性反应的信号通路和生物学后果，在激活p53对P16/PRB途径中寻求细微的差异，这些差异可能解释了这些细胞类型的不同渗透率和模式。使用人类皮肤三个主要恶性肿瘤的验证小鼠模型（基底细胞癌，鳞状细胞癌和黑色素瘤），我们还将测试以下假说，即用T-橄榄鼠预处理可降低紫外线辐照或化学癌症后恶性肿瘤的风险。拟议的体外和体内研究的结果应大大增强我们对通过急性DNA损伤或多个细胞分裂的哺乳动物细胞和皮肤引起的基于端粒的保护反应的理解。这些研究还将探索在没有实际DNA损伤或端粒破坏的情况下，T-Oligos可能诱导这些反应的可能的治疗潜力。