The System of Response to DNA Damage Suppresses Environmental Melanomagenesis

DNA 损伤反应系统抑制环境黑色素瘤生成

• 批准号: 7494464
• 负责人: William K. Kaufmann
• 金额: $ 131.89万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-10 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7494464
• 关键词: System; Response; DNA; Damage; Suppresses

DESCRIPTION (provided by applicant) This program will use a systems biology approach to investigate the mechanism(s) whereby human melanocytes undergo neoplastic transformation, clonal expansion, and malignant progression to cutaneous melanomas. The proposed studies are based on the premise that an environmental carcinogen, solar radiation, contributes to development of melanoma by inducing chromosomal damage in proliferating melanocytes. Malignant melanomas are of significant public health concern because their incidence is rising and no effective medical intervention is available for reducing morbidity and mortality. The guiding hypothesis of this program is that breakdowns in the systems of defense against DNA damage underlie the acquisition by meianocytes of a mutator phenotype, which reduces the effective dose of solar radiation needed to induce each subsequent step in the multi-stage development of cancer. Functional defects in DNA repair and cell cycle checkpoints, individually and in concert, contribute to genome destabilization, and thus increase the probability of accumulation in a single clone of the genetic alterations required for development of melanoma. Three research projects and three service cores will interact extensively to monitor quantitatively and qualitatively the system of response to DNA damage in UV-damaged human and murine melanocytes. Two research projects will determine how nucleotide excision repair, post-replication repair, double-strand break repair, and cell cycle checkpoint responses to UV-induced DNA damage cooperate to suppress chromosomal aberrations and allelic deletions in the melanoma tumor suppressor locus CDKN2A/INK4A. Functional assays will associate chromosomal instability and defective DNA damage responses in melanoma cell lines and melanocytes with alterations in melanomagenic genes. A third research project uses in vivo models of melanoma in mice and humans to monitor chromosomal destabilization during stages of development of melanoma. program investigations will determine how activating mutations in melanoma oncogenes and inactivating mutations in melanoma suppressor genes contribute to chromsomal instability and malignant progression. New findings will lead to the discovery of biomarkers with potential therapeutic and prognostic value for specific types of melanomas and different stages of melanoma progression. Computational models will be created to predict how DNA repair and checkpoint functions suppress UV-induced chromsomal damage. These studies will establish the degree to which melanoma-associated genetic alterations alone and in combinations contribute to a UV-chromosomalmutator phenotype and enhance environmental carcinogenesis. Lessons learned in this program will also impact on methods of risk assessment by showing that the effective dose of a carcinogen falls during the multi-step development of cancer. PROGRAM AS AN INTEGRATED EFFORT

描述（由申请人提供） 该项目将使用系统生物学方法来研究人类黑色素细胞经历肿瘤转化、克隆扩张和皮肤黑色素瘤恶性进展的机制。拟议的研究基于这样的前提：环境致癌物太阳辐射通过诱导增殖的黑素细胞的染色体损伤而促进黑色素瘤的发展。恶性黑色素瘤是一个重大的公共卫生问题，因为它们的发病率正在上升，并且没有有效的医疗干预措施来降低发病率和死亡率。该计划的指导性假设是，DNA损伤防御系统的崩溃是黑素细胞获得突变表型的基础，这减少了诱导癌症多阶段发展中每个后续步骤所需的太阳辐射的有效剂量。 DNA 修复和细胞周期检查点的功能缺陷，无论是单独的还是协同的，都会导致基因组不稳定，从而增加黑色素瘤发展所需的遗传改变在单个克隆中积累的可能性。三个研究项目和三个服务核心将广泛相互作用，以定量和定性监测紫外线损伤的人类和小鼠黑素细胞中 DNA 损伤的反应系统。两个研究项目将确定核苷酸切除修复、复制后修复、双链断裂修复和细胞周期检查点对紫外线诱导的 DNA 损伤的反应如何协同抑制黑色素瘤肿瘤抑制基因座 CDKN2A/INK4A 中的染色体畸变和等位基因缺失。功能测定将黑色素瘤细胞系和黑色素细胞中的染色体不稳定性和缺陷性 DNA 损伤反应与黑色素瘤基因的改变联系起来。第三个研究项目使用小鼠和人类黑色素瘤体内模型来监测黑色素瘤发展阶段的染色体不稳定。计划调查将确定黑色素瘤癌基因的激活突变和黑色素瘤抑制基因的失活突变如何导致染色体不稳定和恶性进展。新的发现将导致发现对特定类型的黑色素瘤和黑色素瘤进展的不同阶段具有潜在治疗和预后价值的生物标志物。将创建计算模型来预测 DNA 修复和检查点功能如何抑制紫外线引起的染色体损伤。这些研究将确定与黑色素瘤相关的遗传改变单独和组合在多大程度上导致紫外线染色体突变表型并增强环境致癌作用。该计划中吸取的经验教训还将通过表明致癌物的有效剂量在癌症的多步骤发展过程中下降而影响风险评估方法。 综合努力的计划