The role of pheomelanin in cutaneous melanoma

褐黑素在皮肤黑色素瘤中的作用

• 批准号: 8012141
• 负责人: Rutao Cui
• 金额: $ 30.76万
• 依托单位: TUFTS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-06-01 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8012141
• 关键词: Cutaneous Melanoma; Role; pheomelanin

DESCRIPTION (provided by applicant): Ultraviolet (UV) radiation represents a definitive risk factor for skin cancer, particularly in combination with certain underlying genetic traits, such as red hair and fair skin. Skin pigmentation results from the synthesis of melanin in pigment-producing cells, the melanocytes, followed by distribution and transport of the pigment granules to neighboring keratinocytes. Epidemiological studies have found less skin cancer in people who have high levels of constitutive pigment and/or tan well. However, we have incomplete understanding of other factors involved in the development of skin cancer, such as capacity to repair photo- damage in people of different skin colors. The finding that albinos have a lower incidence of melanoma than people with fair skin makes this question more complex. Recent findings including our own have led to a realization that melanin, especially pheomelanin (a yellow/red form of melanin), acts as a potent UVB photosensitizer to induce DNA damage and cause apoptosis in mouse skin. The proposed research will focus on the role of pheomelanin in DNA damage, at both genomic and individual nucleotide levels, and on the subsequent activation of DNA repair, alteration in chromatin structure, and ultimately melanoma formation. We hypothesize that pheomelanin contributes to UV-induced DNA damage that is incompletely repaired. Although DNA repair may be activated to a larger extent in response to the greater DNA damage in pheomelanin-containing skin, the repair will be insufficient to eliminate all mutagenic adducts. We will first identify the role of pheomelanin in melanoma formation by melanoma mouse models. Second, we will define the photoproducts and oxidative stress to DNA in mice with different type of epidermal pigmentation at different times after UVB irradiation by quantitative methods. Third, we will map DNA damage in specific sequences of BRAF and N-RAS genes, both of which are frequently mutated in human melanoma. Finally, we will detect the expression of genes in DNA repair pathways at different times after UVB irradiation. Given the vital role that pheomelanin plays in normal phototoxicity and disease, these studies will provide important insights into the homeostasis of tanning and the pathogenesis of disorders like melanoma. Expanding our knowledge of DNA repair in different skin types provides a rich ground for melanoma prevention and for the development of targeted small-molecule therapeutics. PUBLIC HEALTH RELEVANCE: Melanoma prevention is defined as the reduction of melanoma mortality via reduction in the incidence of melanoma. Our results may provide a rich framework for melanoma prevention; and development of targeted small-molecules to induce eumelanin (black/brown), and hence an eventual reduction in incidence of this widely lethal malignancy.

描述（由申请人提供）：紫外线 (UV) 辐射是皮肤癌的明确危险因素，特别是与某些潜在的遗传特征（例如红头发和白皙皮肤）相结合。皮肤色素沉着是由于色素生成细胞（黑素细胞）中黑色素的合成，然后色素颗粒分布并运输到邻近的角质细胞。流行病学研究发现，具有高水平色素和/或晒黑良好的人患皮肤癌的几率较低。然而，我们对涉及皮肤癌发展的其他因素还不完全了解，例如不同肤色的人修复光损伤的能力。白化病患者黑色素瘤发病率低于皮肤白皙的人的发现使这个问题变得更加复杂。最近的发现（包括我们自己的发现）使人们认识到黑色素，尤其是褐黑素（黑色素的黄色/红色形式），可以作为一种有效的 UVB 光敏剂，诱导 DNA 损伤并导致小鼠皮肤细胞凋亡。拟议的研究将重点关注褐黑素在基因组和个体核苷酸水平上的 DNA 损伤中的作用，以及随后的 DNA 修复激活、染色质结构改变以及最终黑色素瘤的形成。我们假设褐黑素会导致紫外线诱导的 DNA 损伤无法完全修复。尽管 DNA 修复可能会在更大程度上被激活，以应对含有褐黑素的皮肤中更大的 DNA 损伤，但修复不足以消除所有诱变加合物。我们将首先通过黑色素瘤小鼠模型确定褐黑素在黑色素瘤形成中的作用。其次，我们将通过定量方法确定不同类型表皮色素沉着小鼠在 UVB 照射后不同时间的光产物和对 DNA 的氧化应激。第三，我们将绘制 BRAF 和 N-RAS 基因特定序列中的 DNA 损伤图谱，这两个基因在人类黑色素瘤中经常发生突变。最后，我们将检测UVB照射后不同时间DNA修复途径中基因的表达情况。鉴于褐黑素在正常光毒性和疾病中发挥的重要作用，这些研究将为晒黑的稳态和黑色素瘤等疾病的发病机制提供重要的见解。扩大我们对不同皮肤类型 DNA 修复的了解，为预防黑色素瘤和开发靶向小分子疗法奠定了丰富的基础。公共卫生相关性：黑色素瘤预防被定义为通过降低黑色素瘤发病率来降低黑色素瘤死亡率。我们的结果可能为黑色素瘤的预防提供丰富的框架；开发有针对性的小分子来诱导真黑素（黑色/棕色），从而最终降低这种广泛致命的恶性肿瘤的发病率。