Epidemiology of protein glutathiolation

描述（由申请人提供）：候选人的长期目标是在香烟烟雾诱导的氧化应激对癌症的贡献方面发展研究专业知识和计划。 提出了一个多学科的教育和指导计划。 这包括分子流行病学，遗传学和相关领域的教学课程，并参加研讨会，专业会议和其他培训机会，主题内容为氧化应激或分子流行病学。 导师制将包括在谷胱甘肽和癌症预防权威John Richie博士和宾夕法尼亚州立大学癌症中心副主任Philip Lazarus博士的指导下进行实践培训和研究指导。 氧化应激的流行病学标志物很少。迄今为止，诸如血液抗氧化剂维生素水平和氧化DMA或脂质损伤的替代标记物已被用于研究癌症中的氧化应激。 然而，这些标志物提供的信息很少，在细胞的氧化还原状态的变化和改变的关键蛋白质参与致癌。 谷胱甘肽氧化为蛋白结合谷胱甘肽（GSSP）被认为是氧化应激的敏感标志物。 我们的初步研究表明，吸烟者的GSSP大幅增加。 中心假设是香烟烟雾自由基引起氧化应激，如通过血液蛋白谷胱甘肽化测量的，并且GSSP水平被氧化应激基因、抗氧化剂和生活方式因素中的多态性修饰。 具体目标是： 1.确定血液中GSSP水平的种族差异，以响应阿利特诱导的氧化应激。 检测饮酒、饮食、MnSOD和HOGG 1基因多态性对血GSSP水平的影响。 2.在病例对照研究中确定肺癌和口腔癌的风险与血液GSSP浓度相关。 对于肺癌，确定与MnSOD多态性相关的风险及其与GSSP的联合作用。 3.进行MAC补充对血液和脱落颊细胞GSSP浓度的随机干预试验。 将GSSP水平与氧化损伤标志物（包括8-OhdG、F-2异前列腺素、蛋白质羰基和血浆维生素抗氧化剂水平）相关联。 在调整年龄、遗传多态性和其他因素后，确定MAC补充剂的效果。

DESCRIPTION (provided by applicant): The long-term goal of the candidate is to develop a research expertise and program in the contribution of cigarette smoke-induced oxidative stress to cancer. A multidisciplinary educational and mentoring program is proposed. This includes didactic courses in molecular epidemiology, genetics and related fields, and participation in workshops, professional conferences, and other training opportunities with a subject content in oxidative stress or molecular epidemiology. Mentorship will include hands-on training and research guidance under Dr. John Richie, an authority on glutathione and cancer prevention, and Dr. Philip Lazarus, Associate Director of the Penn State Cancer Center. There are few reliable epidemiologic markers of oxidative stress. To date proxy markers such as blood antioxidant vitamin levels and oxidative DMA or lipid damage has been used to study oxidative stress in cancer. However, such markers provide little information about changes in the redox status of cells and alterations in critical proteins involved in carcinogenesis. The oxidation of glutathione to protein-bound glutathiolation (GSSP) is proposed as a sensitive marker of oxidative stress. Our preliminary studies demonstrate substantial increases in GSSP in cigarette smokers. The central hypothesis is that cigarette smoke free radicals cause oxidative stress as measured by blood protein glutathiolation, and that GSSP levels are modified by polymorphisms in oxidative stress genes, antioxidants and lifestyle factors. The specific aims are: 1. Determine racial differences in blood GSSP levels in response to cigarette-induced oxidative stress. Measure the effects of alcohol consumption, diet, MnSOD and HOGG1 genetic polymorphisms on blood GSSP levels. 2. Determine the risk of lung and oral cancer associated with blood GSSP concentrations in case-control studies. For lung cancer, determine the risk associated with the MnSOD polymorphism and its joint effect with GSSP. 3. Conduct a randomized intervention trial of MAC supplementation on blood and exfoliated buccal cell GSSP concentrations. Correlate levels of GSSP with markers of oxidative damage including 8-OhdG, F-2 isoprostanes, protein carbonyls, and plasma vitamin antioxidant levels. Determine the effects of MAC supplementation after adjustment for age, genetic polymorphisms and other factors.