Mechanisms of UV-Mediated Melanoma Development

摘要 预防黑色素瘤的生物过程通常是成功的。因此，要了解黑色素瘤 病因学我们必须确定这些导致肿瘤发生的机制中的缺陷。这一建议将阐明 对抗紫外线损伤和确定肿瘤发生后果的细胞机制的缺陷 黑素细胞色素生成。我们的研究将通过以下方式提高对黑色素瘤病因学的机制理解： 揭示了阻止紫外线致癌的生理过程中的缺口。 我们假设黑色素瘤的进展受到黑色素生成的影响，并被黑色素瘤的生长所加速。 未解决的DNA损伤的持久性特定于起始UV波长。为了验证这一假设， 将定义全光谱（UVA/B）和分区太阳辐射（UVA或UVB）如何影响发病， 黑色素瘤在遗传相关的Braf和Nras突变小鼠模型中的进展。我们将阐明 由每个UV光谱和致癌基因驱动的肿瘤中富集的转录和突变模式， 这一信息，以确定如何紫外线损伤逃脱修复（目标1）。接下来，我们将把我们的模型与真黑素模型进行交叉， 黑色素（黑色）、无黑色素（白化病）或褐黑色素（红色/黄色）等位基因，以确定黑色素如何影响 促进Braf和Nras突变型黑色素瘤的形成、进展和免疫应答 不同的UV光谱（目标2）。从这些实验中获得的知识将有助于黑素瘤的发展 除了防晒霜之外，还可以采取干预措施， 暴露或减少黑色素瘤的风险，在个人更感光皮肤类型。

ABSTRACT Biological processes that guard against melanoma are generally successful. Thus, to understand melanoma etiology we must identify the flaws in these mechanisms that lead to tumorigenesis. This proposal will elucidate deficiencies in the cellular mechanisms that combat UV damage and define the tumorigenic consequences of melanocyte pigment production. Our studies will improve mechanistic understanding of melanoma etiology by revealing gaps in the physiological processes that block UV carcinogenesis. We hypothesize that melanoma progression is influenced by melanin production and accelerated by the persistence of unresolved DNA lesions specific to the initiating UV wavelength. To test this hypothesis we will define how full-spectrum (UVA/B) and partitioned solar irradiation (UVA or UVB) influence the onset and progression of melanoma in genetically relevant, Braf- and Nras-mutant mouse models. We will elucidate transcriptional and mutational patterns enriched in tumors driven by each UV spectrum and oncogene, and use this information to define how UV lesions escape repair (Aim 1). Next, we will cross our models to eumelanotic (black), amelanotic (albino) or pheomelanotic (red/yellow) alleles to determine how melanin impacts the formation, progression and immunotherapeutic response of Braf- and Nras-mutant melanomas accelerated by different UV spectra (Aim 2). Knowledge gained from these experiments will aid in the development of melanoma preventatives that progress beyond sunscreens, including interventions that mitigate UV carcinogenesis after an exposure or reduce melanoma risk in individuals with more photosensitive skin types.