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疾病，预计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黑色素瘤的两个主要危险因素。然而，缺乏基因控制实验来建立明确的因果关系。该项目旨在为两个主要目标创建一系列小鼠模型：(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；(2)利用这些小鼠模型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。为了产生一种新的黑色素瘤小鼠模型，正在产生同样携带可激活形式的BRAF或NRAS（黑色素瘤中最常见的突变致癌基因）的红/金发、白化和黑色小鼠。使用该系统的初步实验已经揭示了一个惊人的观察结果，即大量的红色/金色老鼠患上了黑色素瘤，而没有白化老鼠和很少的黑色老鼠患上了相同的病变。这些数据表明，红/金发表型具有很强的遗传致瘤作用，因此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，将比较紫外线照射下红/金发、白化和黑色小鼠的黑色素瘤发病率，以确定色素沉着和单独紫外线的影响。接下来，将比较携带黑色素瘤中最常见的两种突变致癌基因（BRAF或NRAS）之一的紫外线照射黑鼠之间的黑色素瘤发病率，以确定致癌基因激活和紫外线照射的影响。最后，对携带相同突变癌基因的红/金发和白化小鼠进行紫外线照射后的黑色素瘤发病率进行比较，看看这三个变量是如何共同作用来改变黑色素瘤风险的。第二个目标是了解紫外线和红色/金色斑虫诱发疾病的机制。首先，研究人员将调查红/金发人群中黑色素瘤的高发病率是否与色素沉着有关。接下来，我们将探讨红/金发黑色素瘤的机制是否通过反应性氧化损伤，正如之前的研究表明，红/金发色素可以促进反应性氧化物种（reactive oxidative species， ROS）的释放。为了研究这个问题，我们将比较紫外线照射下红/金发、白化和黑色小鼠的DNA损伤类型。最后，将对黑色素细胞中的ROS负荷进行遗传和药理学改变，以研究该策略是否可以阻断红/金发黑色素瘤的诱导。

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.