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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

基本信息

批准号：
9326919
负责人：
Feng Liu-Smith
金额：
$ 12.59万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-09-21 至 2019-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9326919
关键词：
Affect Age BRAF gene Basic Science Biological Biology Biometry Cancer Control Career Choice Case-Control Studies Cell Line Cells Chemoprevention Chronic Code DNA Data Educational process of instructing Elements Environmental Risk Factor Enzymes Epidemiologist Epidemiology Etiology Exhibits Family member Feedback Foundations Gene Family Generations Genes Genetic Genetic Variation Genetic study Genotype Goals Grant Human Incidence Individual International 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 epidemiology study experience genetic variant high risk high risk population keratinocyte kidney cell meetings melanocyte melanoma men mutant novel novel marker oncology overexpression oxidative DNA damage population based skills statistics superoxide dismutase 1 surveillance data symposium translational study tumor undergraduate student

项目摘要

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（Nox 1，Nox 4和p22 phox），SOD（SOD 1，SOD 2和SOD 3）和过氧化氢酶的遗传变异作为黑色素瘤风险因素。这个项目有多个目的：1）作为一个学习平台，让我成为一名癌症流行病学家; 2）测试一个关于紫外线诱导，ROS驱动的黑色素瘤病因机制的新假设; 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Nox通路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。为了实现这些目标，将需要在病原学，流行病学，信号转导和转化肿瘤学的综合知识和技能。该项目汇集了一批成就卓著的导师，他们的专业知识涵盖流行病学、统计学和化学预防。Hoda Anton- Culver博士是一位国际公认的杰出流行病学家，他将是我的主要导师，指导我进行流行病学研究。Ziogas博士（高级生物统计学家）将是我的生物统计学导师。Meyskens博士是一位杰出的、成就卓著的癌症预防专家，他还拥有丰富的黑色素瘤生物学知识，他将指导我完成紫外线诱导的皮肤信号转导研究，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）和流行病学硕士研究; 2）获得流行病学研究的专业知识; 3）扩展我在黑色素瘤肿瘤生物学和癌症预防方面的技能和知识; 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中检查先前在Nox通路中鉴定的功能性SNP与黑色素瘤风险的关联（Aim 1A），以及这些变体如何影响细胞ROS水平、UV诱导的DNA损伤和NRAS癌基因激活的机制研究（Aim 1B）。接下来，我们将评估Nox家族基因的生殖系遗传变异与肿瘤中的NRAS突变之间是否存在关联（目的2）。上述目的联合收割机结合流行病学和机制的理解来研究黑色素瘤病因。这项研究不仅有可能对黑色素瘤的预防和控制产生重大影响，而且对其他癌症类型的研究也具有非常重要的意义，因为ROS已被证明与许多癌症类型的病因学有关。此外，这笔赠款将给我一个很好的机会和保护的时间，建立一个成功的独立的职业道路，作为一个分子流行病学家与强大的基本科学技能。