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）是亚洲许多地方的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，有60万个新案件 和每年死亡。 HCC的影响因诊断的中位年龄在45至 50年，几乎总是致命的。与发展有关的主要已知病因 这些区域的HCC是乙型肝炎（HBV）和/或丙型肝炎（HCV）病毒和寿命的感染 饮食中暴露于高水平的黄曲霉毒素B1（AFB1）。 HCC也是实体瘤最快上升的实体瘤 美国，在少数民族社区中代表过多。虽然对HCC病因的了解刺激了 许多理解该疾病发病机理的机械研究，此信息仅仅是 开始转化为高风险人群预防和临床干预的发展。 该项目的目标是开发和验证反映暴露的生物学作用的生物标志物 在肝癌病因中的化学和病毒毒性。在包括癌症在内的所有慢性人类疾病中 环境暴露于多种环境药物是重要的贡献者。这个特定的目的 项目是：1）为尿尿道毒素代谢物开发经过验证的同位素稀释LC-MS方法： 氧化的黄曲霉毒素；黄曲霉毒素苏联酸；咪唑环开放的Fapy加合物和黄曲霉毒素 - 赖氨酸 加合物； 2）确定丙型肝炎病毒（HBV）和p53在血清DMA中的功能以预测 中国农村和西非人群中的HCC风险； 3）扩展我们对互动的评估 丙型肝炎病毒（HCV），HBV和黄曲霉毒素暴露是HCC发展的风险因素 泰国北部。该项目正在努力为生物标志物开发创新的定量方法 应用于评估一级和化学预防干预措施在高危的疗效 HCC的种群。这些生物标志物已经并且将继续使用队列研究和 然后，它们与疾病风险的关系将被表征。