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: 8376299
• 负责人: John D Groopman
• 金额: $ 40.77万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-06-01 至 2014-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8376299
• 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和死亡的主要原因， 包括中国和泰国，以及撒哈拉以南非洲地区，新增病例超过 60 万例 以及每年的死亡人数。诊断中位年龄在 45 岁至 45 岁之间，加剧了 HCC 的影响 50 年，几乎总是致命的。与发展相关的主要已知病因 这些地区的肝癌是乙型肝炎 (HBV) 和/或丙型肝炎 (HCV) 病毒感染且终生 饮食中暴露于高含量的黄曲霉毒素 B1 (AFB1)。 HCC 也是全球增长最快的实体瘤 美国，并且在少数族裔社区中所占比例过高。虽然对 HCC 病因的了解促使 许多机制研究来了解这种疾病的发病机制，这些信息只是 开始转化为针对高危人群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的生物效应的生物标志物 肝癌病因学中的化学和病毒毒物。在所有慢性人类疾病中，包括癌症， 环境中多种环境因素的暴露是重要的促成因素。本次活动的具体目标 项目包括： 1) 开发经验证的尿黄曲霉毒素代谢物同位素稀释 LC-MS 方法： 氧化黄曲霉毒素；黄曲霉毒素硫醇酸；咪唑环打开的 FAPY 加合物和黄曲霉毒素-赖氨酸 加合物； 2) 确定血清 DMA 中乙型肝炎病毒 (HBV) 和 p53 突变预测的能力 中国农村和西非人群的肝癌风险； 3) 扩展我们对之间相互作用的评估 丙型肝炎病毒（HCV）、乙型肝炎病毒和黄曲霉毒素暴露是一组人群中发生肝癌的危险因素 泰国北部。该项目致力于开发生物标志物的创新定量方法 用于评估高危人群初级和化学预防干预措施的效果 HCC 人群。这些生物标志物已经并将继续通过队列研究和 然后将描述它们与疾病风险的关系。