RESEARCH PROJECT 1: Chemical and Viral Biomarkers of Exposure and Risk (Groopman)

研究项目 1：暴露和风险的化学和病毒生物标志物（Groopman）

• 批准号: 8278588
• 负责人: John D Groopman
• 金额: $ 48.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-06-01 至 2013-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8278588
• 关键词: Acetylcysteine; Aflatoxin B1; Aflatoxins; Africa; Africa South of the Sahara; Age; Apoptosis; Asia; Biological; Biological Markers; Blood; Cancer Etiology; Carcinogens; Cells; Cessation of life; Chemicals; Chemoprevention; China; Chronic; Clinical; Codon Nucleotides; Cohort Studies; Communities; Complex; DNA; Development; Diagnosis; Diet; Disease; Dose; Environmental Exposure; Epidemiologic Studies; Epoxy Compounds; Equilibrium; Etiology; Exposure to; Gene Mutation; Genetic; Goals; Guanine; HBV and Aflatoxin; Hepatitis B; Hepatitis B Virus; Hepatitis C; Hepatitis C virus; Human; Imidazole; Individual; Infection; Intervention; Intervention Trial; Isotopes; Knowledge; Label; Lysine; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Metabolic Pathway; Methodology; Methods; Minority; Molecular; Morbidity - disease rate; Mutation; Nucleotides; Organ; Outcome; Pathogenesis; Population; Predisposition; Prevalence; Preventive; Primary carcinoma of the liver cells; Process; Program Research Project Grants; Proteins; Risk; Risk Factors; Rural; Serum; Short Oligonucleotide Mass Analysis; Site; Solid Neoplasm; Thailand; Time; Toxic Environmental Substances; Translating; Tumor Suppressor Genes; Viral; Viral Genes; Virus; Work; adduct; cohort; disorder risk; environmental agent; high risk; human disease; innovation; insight; mortality; novel; programs; response; success; toxicant; urinary

Hepatocellular carcinoma (HCC) is a major cause of cancer morbidity and mortality in many parts of Asia, including China and Thailand, and in sub-Saharan Africa, where there are upwards of 600,000 new cases and deaths each year. The impact of HCC is exacerbated by a median age of diagnosis of between 45 and 50 years and it is nearly always fatal. The major known etiological factors associated with development of HCC in these regions are infection with hepatitis B (HBV) and/or hepatitis C (HCV) virus and lifetime exposure to high levels of aflatoxin B1 (AFB1) in the diet. HCC is also the most rapidly rising solid tumor in the US and is overrepresented in minority communities. While knowledge of the etiology of HCC has spurred many mechanistic studies to understand the pathogenesis of this disease, this information is only just beginning to be translated into development of preventive and clinical interventions in high risk populations. The goals of this project are to develop and validate biomarkers reflecting the biological effects of exposures to chemical and viral toxicants in the etiology of liver cancer. In all chronic human diseases, including cancer, ambient exposures to multiple environmental agents are significant contributors. The specific aims of this project are: 1) To develop validated isotope dilution LC-MS methods for urinary aflatoxin metabolites: oxidized aflatoxins; aflatoxin mercapturic acid; the imidazole-ring opened FAPY adduct and aflatoxin-lysine adducts; 2) To determine the power of mutations in hepatitis B virus (HBV) and p53 in serum DMA to predict HCC risk in cohorts in rural China and West Africa; and 3) To extend our assessment of interactions among hepatitis C virus (HCV), HBV and aflatoxin exposure as risk factors for HCC development in a cohort in Northern Thailand. This project is working to develop innovative quantitatitive methods for biomarkers that are applied to the assessment of the efficacy of both primary and chemoprevention interventions in high-risk populations for HCC. These biomarkers have been and will continue to be validated using cohort studies and their relation to disease risk will then be characterized.

肝细胞癌（HCC）是亚洲许多地区癌症发病率和死亡率的主要原因， 包括中国和泰国，以及撒哈拉以南非洲，那里有超过60万的新病例， 每年的死亡人数。HCC的影响因诊断的中位年龄在45岁和45岁之间而加剧。 50年，几乎总是致命的。与发展相关的主要已知病因学因素 这些地区的HCC是感染B型肝炎（HBV）和/或丙型肝炎（HCV）病毒， 暴露于饮食中高水平的黄曲霉毒素B1（AFB 1）。肝细胞癌也是世界上增长最快的实体肿瘤 美国，在少数民族社区中的比例过高。虽然对肝细胞癌病因的了解已经促进了 许多机制的研究，以了解这种疾病的发病机制，这一信息只是 开始转化为在高危人群中制定预防和临床干预措施。 该项目的目标是开发和验证反映暴露生物效应的生物标志物 化学和病毒毒素在肝癌病因学中的作用。在所有人类慢性疾病中，包括癌症， 环境中暴露于多种环境因子是重要的因素。具体目标是 项目包括：1）建立尿中黄曲霉毒素代谢物的同位素稀释LC-MS方法： 氧化型黄曲霉毒素、巯基尿酸、咪唑开环FAPY加合物和黄曲霉毒素-赖氨酸 加合物; 2）确定B型肝炎病毒（HBV）突变和血清DMA中p53的能力，以预测 中国农村和西非队列的HCC风险;以及3）扩展我们对以下因素之间相互作用的评估： 丙型肝炎病毒（HCV）、HBV和黄曲霉毒素暴露作为HCC发生的危险因素 泰国北方。该项目致力于开发生物标志物的创新定量方法， 应用于评估原发性和化学预防干预在高危人群中的疗效 肝癌的人群。这些生物标志物已经并将继续使用队列研究进行验证， 然后将描述它们与疾病风险的关系。