The role of pheomelanin in cutaneous melanoma

说明(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相结合，如红发和白皙皮肤。皮肤色素沉着是由产生色素的细胞，即黑素细胞合成黑色素，然后将色素颗粒分布和运输到邻近的角质形成细胞造成的。流行病学研究发现，结构性色素水平高和/或皮肤晒得很好的人患皮肤癌的几率较低。然而，我们对与皮肤癌发生有关的其他因素，如修复不同肤色人的光损伤的能力，了解得不够全面。白化患者的黑色素瘤发病率低于皮肤白皙的人，这一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，使人们意识到黑色素，特别是黑色素(黑色素的一种黄色/红色形式)，作为一种有效的UVB光敏剂，在小鼠皮肤中诱导DNA损伤和细胞凋亡。拟议的研究将集中在基因组和单个核苷酸水平上的黑素在DNA损伤中的作用，以及随后的DNA修复激活，染色质结构的改变，最终黑色素瘤的形成。我们假设褐黑素在紫外线诱导的DNA损伤中起到了作用，但这种损伤尚未完全修复。虽然DNA修复可能会在更大程度上被激活，以回应更大程度的DNA损伤，但修复将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黑色素在黑色素瘤形成中的作用。其次，我们将用定量的方法确定不同类型表皮色素沉着的小鼠在UVB照射后不同时间的光产物和对DNA的氧化应激。第三，我们将在特定的BRAF和N-RAS基因序列中定位DNA损伤，这两个基因在人类黑色素瘤中都经常发生突变。最后，我们将检测UVB照射后不同时间DNA修复途径中的基因表达。鉴于褐黑素在正常的光毒性和疾病中扮演的重要角色，这些研究将为研究晒黑的动态平衡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的DNA修复的了解，为黑色素瘤的预防和靶向小分子疗法的发展提供了丰富的基础。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和靶向小分子的开发提供了丰富的框架，以诱导真黑素(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。

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.