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

描述（由申请人提供）：本职业发展项目主要研究NADPH氧化酶基因家族成员（Nox1， Nox4和p22phox）， sod （SOD1， SOD2和SOD3）和过氧化氢酶的遗传变异作为黑色素瘤的危险因素。这个项目有多重目的：1)作为一个学习平台，让我成为一名癌症流行病学家；2)验证紫外线诱导、ros驱动的黑色素瘤发病机制的新假说；3)为我在黑色素瘤预防方面的长期职业发展奠定基础。我的近期研究目标是了解氮氧化物途径基因在黑色素瘤病因学中的作用。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方面的专家。要实现这些目标，需要在病因学、流行病学、信号转导和转化肿瘤学方面具备综合知识和技能。该项目汇集了一批成绩优异的导师，他们的专业知识涵盖流行病学、统计学和化学预防。国际公认的杰出流行病学家Hoda Anton- Culver博士将是我的主要导师，指导我进行流行病学的研究。Ziogas博士（资深生物统计学家）将是我的生物统计学导师。Meyskens博士是一位杰出的癌症预防专家，在黑色素瘤生物学方面也有广泛的知识，他将指导我进行紫外线诱导的皮肤信号转导的研究，并将结果应用于转化研究。我的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）和流行病学理学硕士研究；2)获得流行病学研究方面的专业知识；3)拓展自己在黑色素瘤肿瘤生物学和防癌方面的技能和知识；4)积累本科生指导和教学经验。该项目的第一个目的是在一项基于人群的病例对照研究（aim 1A）中检查Nox途径中先前确定的功能性snp与黑色素瘤风险的关联，以及这些变异如何影响细胞ROS水平、紫外线诱导的DNA损伤和NRAS癌基因激活（aim 1B）的机制研究。接下来，我们将评估肿瘤中Nox家族基因的种系遗传变异与NRAS突变之间是否存在关联（目的2）。上述目的结合流行病学和机理的认识来研究黑色素瘤的病因。这项研究不仅对黑色素瘤的预防和控制具有潜在的重大影响，而且对其他癌症类型的研究也具有重要意义，因为ROS已被证明与许多癌症类型的病因有关。此外，这笔资助将给我一个极好的机会和保护时间，使我能够建立一个成功的独立的职业道路，成为一名具有较强基础科学技能的分子流行病学家。

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.