Epidemiology of protein glutathiolation

蛋白质谷胱甘肽化的流行病学

• 批准号: 6920839
• 负责人: JOSHUA E MUSCAT
• 金额: $ 13.62万
• 依托单位: PENNSYLVANIA STATE UNIV HERSHEY MED CTR
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-09-06 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6920839
• 关键词: acetylcysteine; alcoholic beverage consumption; antioxidants; biomarker; cancer risk; chemical related neoplasm /cancer; clinical research; clinical trials; diet therapy; dietary aminoacid; dietary supplements; genetic polymorphism; glutathione; human subject; lifestyle; lung neoplasms; molecular oncology; mouth neoplasms; neoplasm /cancer epidemiology; nutrition related tag; oxidative stress; patient oriented research; questionnaires; racial /ethnic difference; smoking; superoxide dismutase; tobacco abuse; tocopherols

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.

描述（由申请人提供）：候选人的长期目标是开发香烟烟雾诱导的氧化应激对癌症的影响的研究专业知识和计划。 提出了多学科教育和指导计划。 这包括分子流行病学、遗传学和相关领域的教学课程，以及参加研讨会、专业会议和其他以氧化应激或分子流行病学为主题的培训机会。 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。 氧化应激的可靠流行病学标志物很少。迄今为止，血液抗氧化维生素水平和氧化 DMA 或脂质损伤等代理标志物已被用于研究癌症中的氧化应激。 然而，此类标记物提供的有关细胞氧化还原状态变化和致癌过程中关键蛋白质变化的信息很少。 谷胱甘肽氧化成蛋白质结合谷胱甘肽（GSSP）被认为是氧化应激的敏感标记。 我们的初步研究表明，吸烟者的 GSSP 显着增加。 核心假设是，通过血液蛋白谷胱甘肽化测量，香烟烟雾自由基会引起氧化应激，并且氧化应激基因、抗氧化剂和生活方式因素的多态性会改变 GSSP 水平。 具体目标是： 1. 确定响应香烟引起的氧化应激的血液 GSSP 水平的种族差异。 测量饮酒、饮食、MnSOD 和 HOGG1 基因多态性对血液 GSSP 水平的影响。 2. 在病例对照研究中确定与血液 GSSP 浓度相关的肺癌和口腔癌风险。 对于肺癌，确定与 MnSOD 多态性相关的风险及其与 GSSP 的联合效应。 3. 进行 MAC 补充剂对血液和脱落口腔细胞 GSSP 浓度影响的随机干预试验。 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。 调整年龄、遗传多态性和其他因素后确定 MAC 补充剂的效果。