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

UVA照射对黑素细胞干细胞的影响及其与发育的关系

基本信息

批准号：
8537732
负责人：
James Douglas Hoerter
金额：
$ 5.45万
依托单位：
FERRIS STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-09-01 至 2013-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8537732
关键词：
Accounting Adult American BRAF gene Cell Aging Cells DNA Repair Dermal Development Devices Disease Early Diagnosis Environmental Carcinogens Etiology Event Exposure to Fishes Goals Health Hour Human Incidence Lesion Maintenance Malignant Neoplasms Melanocytic Neoplasm Melanophores Methods Modeling Mole the mammal Molecular Mutate Mutation Natural regeneration Nevus Normal tissue morphology Oncogenic Pathway interactions Persons Pharmaceutical Preparations Play Prevention Prevention strategy Process Research Research Project Grants Role Skin Skin Cancer Skin tanning Source Staging Stem cells Sunlight Testing Transgenic Organisms UVA induced Ultraviolet A radiation Ultraviolet Rays United States Work Zebrafish base beta-Galactosidase cell transformation design founder mutation in vivo irradiation melanocyte melanoma prevent programs senescence treatment strategy tumor

项目摘要

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.

描述（由申请人提供）：黑色素瘤是人类皮肤癌中最致命的一种。据估计，每小时就有一名美国人死于黑素瘤。然而，黑色素瘤是一种高度可治愈的疾病时，在早期阶段检测。确定黑色素瘤的病因和其发展中涉及的早期机制将允许早期检测和设计更有效的药物来治疗它并防止其复发。这项研究的长期目标是确定恶性黑色素瘤发展的早期分子事件。阳光紫外线辐射（UV）是已知与黑色素瘤有关的主要环境致癌物。太阳光谱中的UVA波长（320-400 nm）现在似乎在黑色素瘤中发挥着比以前认为的更重要的作用。这项建议的主要目的是确定黑素细胞干细胞的UVA照射是否会增加成人黑素细胞肿瘤的发病率。中心假设是，穿透性更强的UVA辐射到达皮肤的真皮层，并导致黑素细胞干细胞或其转运放大细胞发生突变，从而促成黑素瘤的早期阶段。该项目将使用最近在斑马鱼中发现的方法来消除成年黑色素细胞并使黑色素细胞干细胞的黑色素细胞再生同步，以确定黑色素细胞干细胞的UVA照射是否会增加黑色素细胞肿瘤的发病率。具有黑色素瘤的人BRAF创始者突变的人黑色素瘤转基因斑马鱼模型将用于实现以下特定目标：（1）确定黑素细胞干细胞的UVA照射是否会增加痣（痣）中黑素细胞增殖的发生率和黑素瘤的发展，以及从这些被照射的干细胞衍生的再生的成人黑色素细胞的额外UVA照射是否会增加黑色素瘤的发病率，和（2）确定在痣或肿瘤中通过UVA照射黑素细胞干细胞或成年黑素细胞是否抑制了细胞衰老，已知细胞衰老是防止过度增殖的强有力的肿瘤抑制过程。这项研究的结果将有助于揭示导致黑色素瘤发展的早期机制，并确定黑色素细胞干细胞的UVA辐射是否在这一过程中起重要作用。公共卫生关系：这项研究项目将有助于确定如何暴露于阳光和人工光源的阳光，如晒黑和光疗设备有助于早期事件的发展黑色素瘤。它将确定暴露在UVA波长下是否会使黑素细胞干细胞突变并有助于黑色素瘤的发展。了解黑色素瘤的早期事件将允许早期检测和开发更有效的药物来治疗它并防止它复发。