Effect of UVA Irradiation on Melanocyte Stem Cells and Relationship to Developmen

描述(申请人提供)：黑色素瘤是人类皮肤癌中最致命的一种。据估计，每小时有一名美国人死于黑色素瘤。然而，黑色素瘤是一种早期发现的高度可治愈的疾病。确定黑色素瘤的病因和与其发展相关的早期机制将有助于及早发现和设计更有效的药物来治疗黑色素瘤并防止其复发。这项研究的长期目标是确定导致恶性黑色素瘤发展的早期分子事件。阳光紫外线辐射(UV)是已知的与黑色素瘤有关的主要环境致癌物质。太阳光谱的UVA波长(320-400纳米)现在似乎在黑色素瘤中扮演着比之前认为的更重要的角色。这项建议的主要目的是确定UVA照射黑素细胞干细胞是否会增加成人黑素细胞肿瘤的发生率。中心假设是，更具穿透性的UVA辐射到达皮肤的真皮层，导致黑素细胞干细胞或其运输放大细胞发生突变，从而导致黑色素瘤的早期阶段。该项目将使用斑马鱼最近发现的一种方法来消除成年黑素细胞，并同步黑素细胞干细胞的再生，以确定黑素细胞干细胞的UVA辐射是否会增加黑素细胞肿瘤的发生率。转BRAF基因的人黑色素瘤斑马鱼模型将被用于实现下列特定目标：(1)确定黑素细胞干细胞的UVA照射是否会增加色素痣(Moles)中的黑素细胞增殖和黑色素瘤的发生，以及额外的UVA照射是否会增加黑色素瘤的发病率；(2)确定黑素细胞干细胞或成年黑素细胞的UVA照射是否会抑制黑色素瘤的细胞衰老(已知这是一种强大的肿瘤抑制过程，可防止过度增殖)。这项研究的结果将有助于揭开黑色素瘤发生的早期机制，并确定黑素细胞干细胞的UVA辐射是否在这一过程中发挥重要作用。 公共卫生相关性：这项研究项目将有助于确定暴露在阳光下和人造阳光来源，如晒黑和光疗设备如何有助于黑色素瘤发展的早期事件。它将确定暴露在UVA波长下是否会突变黑素细胞干细胞，并有助于黑色素瘤的发展。了解黑色素瘤的早期事件将有助于更早地发现和开发更有效的药物来治疗黑色素瘤并防止其复发。

DESCRIPTION (provided by applicant): Melanoma is the most deadly form of human skin cancer. It is estimated that one American dies from melanoma every hour. However, melanoma is a highly curable disease when detected at early stages. Determining the etiology of melanoma and the early mechanisms involved in its development will permit earlier detection and design of more effective drugs to treat it and prevent its reoccurrence. The long-range goal of this research is to identify the early molecular events responsible for the development of malignant melanoma. Sunlight ultraviolet radiation (UV) is the prominent environmental carcinogen known to be involved in melanoma. The UVA wavelengths (320-400 nm) of the solar spectrum now seem to play a much more important role in melanoma than previous thought. The primary objective of this proposal is to determine if UVA irradiation of melanocyte stem cells increases the incidence of melanocyte tumors in the adult. The central hypothesis is that the more penetrating UVA radiation reaches the dermal layer of the skin and causes mutations in the melanocyte stem cell or in its transit amplifying cells thereby contributing to the early stages of melanoma. This project will use a recently discovered method in zebra fish for eliminating adult melanophores and synchronizing melanocyte regeneration from melanocyte stem cells to determine if UVA irradiation of melanocyte stem cells will increase the incidence of melanocytic tumors. The transgenic zebra fish model for human melanoma which has the human BRAF founder mutation for melanoma will be used to accomplish the following specific aims: (1) determine if UVA irradiation of melanocyte stem cells will increase the incidence of melanocyte proliferations in nevi (moles) and the development of melanoma, and whether additional UVA irradiation of the regenerated adult melanocytes derived from these irradiated stem cells will increase the incidence melanoma, and (2) determine if cellular senescence, known to be a powerful tumor-suppressive process that prevents excessive proliferation, is suppressed in nevi or tumors by UVA irradiation of either melanocyte stem cells or adult melanocytes. The results of this research will help to unravel the early mechanisms that contribute to the development of melanoma, and determine if UVA radiation of melanocyte stem cells plays an important role in this process. PUBLIC HEALTH RELEVANCE: This research project will help determine how exposure to sunlight and artificial sources of sunlight such as tanning and phototherapeutic devices contribute to the early events in the development of melanoma. It will determine if exposure to the UVA wavelengths will mutate melanocyte stem cells and contribute to the development of melanoma. Understanding the early events in melanoma will permit earlier detection and development of more effective drugs to treat it and prevent it reoccurrence.