Molecular Mechanism of UV Protection in Cutaneous Melanoma

项目摘要 来自阳光的紫外线辐射（UVR）已被流行病学确定为以下疾病的主要风险因素： 黑色素瘤发展。然而，阳光紫外线辐射如何导致黑色素瘤的机制细节仍然是 正在澄清。最近的研究揭示了大量的紫外线诱导的基因突变， 黑色素瘤基因组与大多数其他类型的肿瘤相比。此外，紫外线诱导的诱变 加速黑色素瘤进展和复发。这些研究强调，需要更好地 了解保护免受环境紫外线诱导的诱变的分子机制， 描述为什么他们不能在黑色素瘤中工作，提供答案，为个性化治疗铺平道路。 预防和治疗这种经常致命的疾病。这个项目将迎接这一挑战，利用我们的 最近发现一种自噬调节剂通过不同的机制作为真正的紫外线保护剂， 它与降低黑色素瘤风险的密切相关性。我们的主要假设是，紫外线的能力降低- 诱导的光损伤修复和适应性皮肤色素沉着是遗传不稳定的主要原因 是黑色素瘤细胞的生长因子，也是黑色素瘤易感性的原因。为了验证这个假设，我们首先 剖析紫外线诱导的光损伤在黑素细胞中修复的机制， 抵抗（目的1），确定机制，管理紫外线诱导的黑色素生成和色素沉着， 防止紫外线渗透（目标2），并确定这些作用机制如何以及在多大程度上影响 诱导型转基因人源化小鼠黑色素瘤的紫外线敏感性和肿瘤扩展 模型（目标3）。这些目标将通过多学科创新方法来实现， 最先进的遗传学、生物化学、活细胞成像和细胞和小鼠中的生理学测定， 紫外线抗性基因的靶向突变。总之，我们预计我们的研究将确定新的紫外线- 保护机制，调节黑色素瘤疾病的发病率，并提供令人信服的体内 黑色素瘤中新的预后和预测生物标志物的验证。

Project Summary Ultraviolet radiation (UVR) from sunlight has been epidemiologically identified as a leading risk factor for melanoma development. However, the mechanistic details of how sunlight UVR causes melanoma are still being elucidated. Recent studies revealed tremendous amounts of UV-induced genetic mutations in melanoma genomes compared to most other types of tumors. Furthermore, UV-induced mutagenesis accelerates melanoma progression and recurrence. These studies highlighted the need to better understand the molecular mechanisms protecting against environmentally UVR-induced mutagenesis, and to delineate why they fail to work in melanoma, providing answers that could pave the way for personalized prevention and treatment of this often-fatal illness. This project will meet this challenge, capitalizing on our recent discovery of an autophagy modulator as a bona fide UV protector through distinct mechanisms and its strong correlation with reduced melanoma risk. Our primary hypothesis is that reduced capacity of UV- induced photolesion repair and adaptive skin pigmentation represents the main reasons of genetic instability of melanoma cells and is responsible for melanoma predisposition. To test the hypothesis, we will first dissect the mechanism by which UV-induced photolesion is repaired in melanocytes to provide UV resistance (Aim 1), identify the mechanism governing UV-induced melanogenesis and pigmentation to prevent UV penetration (Aim 2), and determine how and to what extent these mechanisms of action impact UV sensitivity and neoplastic expansion of melanoma using inducible transgenic and humanized murine models (Aim 3). These aims will be addressed using multidisciplinary innovative approaches that integrate state-of-the-art genetic, biochemistry, live-cell imaging, and physiological assays in cells and in mice with targeted mutations in UV resistance genes. Together, we anticipate that our studies will identify new UV- protecting mechanisms that regulate melanoma disease penetrance and provide compelling in vivo validation of a novel prognostic and predictive biomarker in melanoma.