The role of pheomelanin in cutaneous melanoma

描述（由申请人提供）：紫外线（UV）辐射是皮肤癌的确定风险因素，特别是与某些潜在遗传特征（如红头发和白皙皮肤）相结合。皮肤色素沉着是由色素产生细胞（黑素细胞）中黑色素的合成，随后色素颗粒分布和运输到邻近的角质形成细胞引起的。流行病学研究发现，具有高水平的组成性色素和/或晒黑的人较少患皮肤癌。然而，我们对皮肤癌发展中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。白化病人患黑色素瘤的发病率低于白皮肤的人，这一发现使这个问题变得更加复杂。最近的研究结果，包括我们自己的已经导致认识到，黑色素，特别是褐黑素（一种黄色/红色形式的黑色素），作为一种有效的UVB光敏剂，诱导小鼠皮肤中的DNA损伤和细胞凋亡。拟议的研究将集中在褐黑素在DNA损伤中的作用，在基因组和单个核苷酸水平，以及随后的DNA修复激活，染色质结构的改变，并最终黑色素瘤的形成。我们推测，褐黑素有助于紫外线诱导的DNA损伤是不完全修复。虽然DNA修复可能会在更大程度上被激活，以响应含有褐黑素的皮肤中更大的DNA损伤，但修复将不足以消除所有致突变加合物。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，我们将通过定量的方法来确定UVB照射后不同类型表皮色素沉着小鼠在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，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。鉴于褐黑素在正常的光毒性和疾病中起着至关重要的作用，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中DNA修复的了解，为黑色素瘤预防和靶向小分子疗法的开发提供了丰富的基础。公共卫生相关性：黑色素瘤预防定义为通过降低黑色素瘤发病率来降低黑色素瘤死亡率。我们的研究结果可能为黑色素瘤的预防提供了一个丰富的框架，并开发了靶向小分子来诱导真黑素（黑色/棕色），从而最终降低了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.