The role of ultraviolet radiation and skin pigmentation in melanoma development

描述（由申请人提供）：转移性黑色素瘤是一种致命的疾病，预期5年生存率仅为14%。该项目的目标是更好地了解导致这种经常致命的疾病的环境和遗传因素，希望我们可以提出疾病预防和治疗干预的方法。流行病学表明，紫外线（UV）辐射和红/金发，皮肤白皙的色素沉着表型是两个主要的黑色素瘤风险因素。然而，缺乏建立明确的因果关系的遗传控制实验。该项目旨在创建一系列小鼠模型，以实现两个主要目标：（1）建立紫外线，色素沉着和黑色素瘤之间的明确联系，以提供更好的公共卫生信息，以及（2）使用这些小鼠模型来了解紫外线和高风险色素沉着变体产生黑色素瘤的分子机制。 为了产生新的黑素瘤小鼠模型，正在产生还携带BRAF或NRAS（黑素瘤中最常见的突变癌基因）的可活化形式的红/金发、白化病和黑色小鼠。使用该系统的初步实验已经揭示了惊人的观察结果，即相当数量的红/金发小鼠发展为黑色素瘤，而没有白化病小鼠和极少数的黑小鼠发展为相同的病变。这些数据表明，红/金发表型具有强烈的遗传致瘤效应，研究紫外线的作用可能会提供令人兴奋的新信息。 为了实现第一个目标，将比较UV照射的红/金发小鼠、白化病小鼠和黑小鼠之间的黑色素瘤率，以确定色素沉着和单独UV的影响。接下来，将比较携带黑色素瘤中2种最常见突变癌基因（BRAF或NRAS）之一的经UV照射的黑小鼠之间的黑色素瘤发生率，以确定癌基因活化和UV照射的影响。最后，将对携带相同突变致癌基因的红/金发小鼠和白化病小鼠进行紫外线照射后的黑色素瘤发生率进行比较，以了解3个变量如何共同作用以改变黑色素瘤风险。 第二个目标是了解紫外线和红/金发表型诱导疾病的机制。最初将研究红/金发背景下黑色素瘤的高发生率是否依赖于色素沉着。接下来，将研究红色/金色黑色素瘤的机制是否是通过反应性氧化损伤，如先前的研究所示，红色/金色色素可以促进反应性氧化物质（ROS）的释放。为了研究这个问题，将比较紫外线照射的红/金发小鼠、白化病小鼠和黑小鼠的DNA损伤类型。最后，黑素细胞中的ROS负荷将被遗传和微生物学改变，以研究这种策略是否可以阻断红色/金色黑色素瘤诱导。 公共卫生相关性：转移性黑色素瘤是一种致命的疾病，预期5年生存率仅为14%。令人担忧的是，在美国，黑色素瘤的发病率上升速度比任何其他恶性肿瘤都快。这个项目的目标是更好地了解环境和遗传因素，有助于发展这种往往致命的疾病，希望我们可以利用这些知识，提出预防疾病的方法和治疗干预的节点

DESCRIPTION (provided by applicant): Metastatic melanoma is a deadly disease with an expected five-year survival of only 14%. The goal of this project is to better understand the environmental and genetic factors which cause this often-fatal disease in the hope that we may suggest approaches for disease prevention and therapeutic intervention Epidemiology has suggested that ultraviolet (UV) radiation and the red/blond, fair-skinned pigmentation phenotype are two major melanoma risk factors. However, genetically controlled experiments to establish an unambiguous causative link is lacking. This project aims to create a series of mouse models for two main objectives: (1) to establish a clear link between UV, pigmentation and melanoma in order to provide better public health information, and (2) to use these mouse models to understand the molecular mechanisms by which UV and high risk pigmentation variants produce melanoma. In order to produce a novel melanoma mouse model, red/blond, albino, and black mice which also carry an activatable form of BRAF or NRAS (the most commonly mutated oncogenes in melanoma) are being generated. Preliminary experiments using this system have already revealed the striking observation that a significant number of the red/blond mice develop melanomas, while none of the albino mice and very few of the black mice develop the same lesions. With this data suggesting there is a strong genetic tumorogenic effect of the red/blond phenotype, it is likely that examining the role of UV will provide exciting new information. To pursue the first aim, melanoma rates between UV irradiated red/blond, albino, and black mice will be compared to determine the effects of pigmentation and UV alone. Next, melanoma rates between UV irradiated black mice that carry either of the 2 most commonly mutated oncogenes in melanoma (BRAF or NRAS) will be compared to determine the effects of oncogene activation and UV irradiation. Lastly, melanoma rates after UV irradiation of red/blond and albino mice carrying the same mutated oncogenes will be compared to see how the 3 variables work together to alter melanoma risk. The goal of the second aim is to understand the mechanisms by which UV and the red/blond phenotpye induce disease. Initially it will be investigated if the high rate of melanoma in the red/blond context is pigmentation dependent. Next, it will be investigated if the mechanism of red/blond-melanoma is via reactive oxidative damage, as suggested by previous studies showing that red/blond pigment can promote release of reactive oxidative species (ROS). To investigate this question, the types of DNA damage in UV irradiated red/blond, albino, and black mice will be compared. Finally, the ROS burden in melanocytes will be genetically and pharmacologically altered to investigate if this strategy can block red/blond-melanoma induction. PUBLIC HEALTH RELEVANCE: Metastatic melanoma is a deadly disease with an expected five-year survival of only 14%. Alarmingly, in the United States, the incidence of melanoma is rising at a faster rate than any other malignancy. The goal of this project is to better understand the environmental and genetic factors that contribute to development of this often-fatal disease, in the hope that we may use this knowledge to suggest approaches for disease prevention and nodal points for therapeutic intervention