Melanoma Risk: Interactions between UV Radiation and NADPH Oxidase Gene Family

黑色素瘤风险：紫外线辐射与 NADPH 氧化酶基因家族之间的相互作用

• 批准号: 8442764
• 负责人: Feng Liu-Smith
• 金额: $ 13.46万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-09-21 至 2018-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8442764
• 关键词: Affect; Age; BRAF gene; Basic Science; Biological; Biological Markers; Biology; Biometry; Cancer Control; Case-Control Studies; Cell Line; Cells; Chemoprevention; Code; DNA; Data; Educational process of instructing; Elements; Environmental Risk Factor; Enzymes; Epidemiologic Studies; Epidemiologist; Epidemiology; Etiology; Exhibits; Family member; Feedback; Figs - dietary; Foundations; Gene Family; Generations; Genes; Genetic; Genetic Variation; Genotype; Goals; Grant; Human; Incidence; Individual; Knowledge; Learning; Link; Literature; Logistic Regressions; Malignant Neoplasms; Master of Science; Mediating; Melanoma Cell; Mentors; Modeling; Molecular; Mutation; NADPH Oxidase; Odds Ratio; Oncogene Activation; Oxidases; Oxidative Stress; Pathway interactions; Patients; Pattern; Play; Population; Prevention; Promoter Regions; Rattus; Reactive Oxygen Species; Research; Risk; Risk Factors; Role; SEER Program; SOD2 gene; Sampling; Scientist; Signal Transduction; Site; Skin; Skin Cancer; Somatic Mutation; Source; Subgroup; Superoxide Dismutase; Superoxides; Techniques; Testing; The Sun; Time; Training; Translating; Tumor Biology; UV induced; UV induced DNA damage; UV-induced melanoma; Ultraviolet Rays; Variant; Woman; base; cancer prevention; cancer type; career; career development; catalase; experience; genetic variant; high risk; human CYBA protein; keratinocyte; kidney cell; meetings; melanocyte; melanoma; men; mutant; novel; oncology; oxidative DNA damage; population based; skills; statistics; symposium; translational study; tumor; undergraduate student

DESCRIPTION (provided by applicant): This career development project is focused on studying genetic variations in NADPH Oxidase gene family members (Nox1, Nox4 and p22phox), SODs (SOD1, SOD2 and SOD3) and catalase as melanoma risk factors. This project serves multiple purposes: 1) as a learning platform for me to be trained as a cancer epidemiologist; 2) to test a novel hypothesis on UV-induced, ROS-driven mechanism of melanoma etiology; and 3) to lay out a foundation for my long-term career development on melanoma prevention. My immediate research goal is to understand the role of the Nox pathway genes in melanoma etiology. My long-term career goal is to become an expert in melanoma epidemiology, cancer control and targeted chemoprevention. To achieve these goals will require integrated knowledge and skills in etiology, epidemiology, signal transduction and translational oncology. This project brings together a group of well achieved mentors whose expertise covers epidemiology, statistics and chemoprevention. Dr. Hoda Anton- Culver, an internationally recognized outstanding epidemiologist will be my primary mentor and guide me through studies on epidemiology. Dr. Ziogas (a senior biostatistician) will be my biostatistics mentor. Dr. Meyskens an outstanding and well-achieved cancer prevention expert, who also possess extensive knowledge on melanoma biology, will guide me through studies on UV-induced skin signal transduction and applying the results to translational studies. The key elements of my career development activities include: 1) Didactic training (seminars, conferences, meetings with mentors) and Master of Science studies in Epidemiology; 2) Acquire expertise in epidemiology research; 3) Expand my skills and knowledge in melanoma tumor biology and cancer prevention; 4) Acquire experience in mentoring undergraduate students and teaching. The first aim of this project is to examine the association of previously identified functional SNPs in Nox pathway with melanoma risk in a population-based case-control study (Aim 1A), as well as mechanistic study of how these variants affect the cellular ROS levels, UV-induced DNA damage and NRAS oncogene activation (Aim 1B). Next we will evaluate whether there is an association between germline genetic variants of Nox family genes with NRAS mutations in the tumors (Aim 2). The aims above combine both epidemiologic and mechanistic understanding to study melanoma etiology. This study not only has the potential of a significant impact on melanoma prevention and control, it will also be of preeminent importance to research on other cancer types as ROS has been demonstrated to be associated with the etiology of many cancer types. Furthermore, this grant will give me an excellent opportunity and protected time to establish a successful independent career path as a molecular epidemiologist with strong basic science skills.

描述（由申请人提供）：该职业发展项目的重点是研究NADPH氧化酶基因家族成员（NOX1，NOX4和P22Phox）的遗传变异，SOD（SOD1，SOD2和SOD2和SOD2和SOD2和SOD2）和催化酶是黑色素瘤风险因素。该项目具有多种目的：1）作为我作为癌症流行病学家培训的学习平台； 2）检验了关于黑色素瘤病因的紫外线诱导的，ROS驱动的机制的新假设； 3）为我在预防黑色素瘤的长期职业发展奠定了基础。我的直接研究目标是了解NOX途径基因在黑色素瘤病因中的作用。我的长期职业目标是成为黑色素瘤流行病学，癌症控制和靶向化学预防的专家。为了实现这些目标，将需要病因，流行病学，信号转导和翻译肿瘤学方面的综合知识和技能。该项目汇集了一群成就良好的导师，其专业知识涵盖了流行病学，统计和化学预防。国际认可的杰出流行病学家Hoda Antonculver博士将是我的主要导师，并通过有关流行病学的研究来指导我。 Ziogas博士（一位高级生物统计学家）将是我的生物统计学导师。 Meyskens博士是一位出色且良好的预防癌症专家，他们还对黑色素瘤生物学具有广泛的知识，将通过对紫外线诱导的皮肤信号转导的研究来指导我，并将结果应用于翻译研究。我职业发展活动的关键要素包括：1）教学培训（研讨会，会议，与导师的会议）和流行病学科学硕士； 2）获得流行病学研究专业知识； 3）扩大我在黑色素瘤肿瘤生物学和预防癌症方面的技能和知识； 4）获得指导本科生和教学的经验。该项目的第一个目的是在基于人群的病例对照研究（AIM 1A）中检查NOX途径中先前鉴定的功能SNP与黑色素瘤风险的关联，以及对这些变体如何影响细胞ROS水平的机械研究，UV诱导的DNA损伤和NRAS ONCOGENE ONCEN ONCEN ONCEN ONCONICATION（AIM 1B）。接下来，我们将评估NOX家族基因的种系遗传变异与肿瘤中NRAS突变之间是否存在关联（AIM 2）。上面的目的结合了流行病学和机械理解，以研究黑色素瘤的病因。这项研究不仅对预防黑色素瘤和控制具有重大影响，而且对于其他癌症类型的研究也将非常重要，因为已经证明ROS与许多癌症类型的病因相关。此外，这笔赠款将为我提供一个绝佳的机会和保护时间，以建立具有强大基础科学技能的分子流行病学家，建立成功的独立职业道路。