Epidemiology of protein glutathiolation

描述（由申请人提供）：候选人的长期目标是在香烟引起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，以及参加以氧化应激或分子流行病学为主题的讲习班、专业会议和其他培训机会。指导将包括在谷胱甘肽和癌症预防方面的权威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。很少有可靠的氧化应激流行病学标志物。迄今为止，诸如血液抗氧化维生素水平和氧化DMA或脂质损伤等代理标记物已被用于研究癌症中的氧化应激。然而，这些标记提供的信息很少关于细胞氧化还原状态的变化和致癌过程中关键蛋白的改变。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。我们的初步研究表明吸烟者的GSSP显著增加。研究的核心假设是，通过测量血液中谷胱甘肽的含量，香烟中的自由基会导致氧化应激，而GSSP的水平会受到氧化应激基因、抗氧化剂和生活方式因素的多态性的影响。

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.