Role of Base Excision Repair in Limiting Hepatocellular Carcinomas -Administrative Supplement

碱基切除修复在限制肝细胞癌中的作用 - 行政补充

• 批准号: 10378947
• 负责人: R. Stephen Lloyd
• 金额: $ 22.25万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-01 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378947
• 关键词: Administrative Supplement; Affect; Aflatoxin B1; Aflatoxins; Africa South of the Sahara; Americas; Automobile Driving; Base Excision Repairs; Biochemical; Biochemical Pathway; Biological; CRISPR/Cas technology; Cancer Etiology; Cell Line; Cells; Central America; Cessation of life; China; Chronic; Complex; County; DNA; DNA Adducts; DNA Binding; DNA Damage; DNA Repair; DNA Repair Disorder; DNA Repair Pathway; DNA Sequence; DNA glycosylase; DNA sequencing; Data; Databases; Development; Diagnostic; Disease; Engineering; Environmental Health; Environmental Risk Factor; Etiology; European; Event; Excision; Exposure to; Fapy-dG; Far East; Frequencies; Funding; Genetic Predisposition to Disease; Genetic Variation; Genotype; Geographic Distribution; Geography; Goals; Grain; Health; Hepatitis B; Hepatitis B Incidence; Hepatitis B Surface Antigens; Hepatitis B Virus; Heterozygote; Human; Incidence; Individual; Inflammation; Ingestion; Investigation; Knock-out; Knowledge; Laboratories; Liver; Liver neoplasms; Malignant Neoplasms; Malignant neoplasm of liver; Measures; Molecular; Mus; Mutagenesis; Mutation; Mycotoxins; Nucleotide Excision Repair; Nucleotides; Nuts; Oncogenic; Onset of illness; Pathway interactions; Phenotype; Population; Populations at Risk; Predisposition; Primary carcinoma of the liver cells; Property; Proteins; Reaction; Reporting; Risk; Risk Factors; Role; South America; Structure; Surface Antigens; Testing; Tissues; Transgenic Mice; Translating; Variant; Virus Diseases; adduct; aflatoxin B1-DNA adduct; base; carcinogenesis; cohort; design; dietary; early onset; effective therapy; epidemiology study; exome sequencing; fungus; gene repair; genetic risk factor; genetic variant; genotoxicity; global environment; global health; mortality; mouse model; population based; primary endpoint; repair enzyme; repaired; response; stressor; tool; tumor DNA; virtual

Summary for Administrative Supplemental Funding Request The combination of chronic dietary exposure to the fungal toxin, aflatoxin B1 (AFB1), and hepatitis B viral (HBV) infection is associated with a significant increased risk for early onset hepatocellular carcinomas (HCCs) in millions of people living in East Asia, Central and South America, and sub-Saharan Africa. Even though dietary exposures to aflatoxins constitute the second largest global environmental risk factor for cancer development, there are still significant questions concerning the molecular mechanisms driving carcinogenesis. In-depth knowledge of these mechanisms is critical for the identification of genetic risk factors that affect individual susceptibility for people who are HBV infected and AFB1 exposed. In this regard, since AFB1 carcinogenesis is driven by high frequency mutagenesis of G to T transversions, the DNA repair pathways that initiate and complete repair of persistent AFB1-induced DNA adducts and base damage from HBV-induced inflammation have strong biological significance. These pathways define the mutagenic burden in the target tissues and ultimately limit cellular progression to cancer. Although the nucleotide excision repair (NER) pathway has been shown to repair AFB1 DNA adducts, murine data presented herein demonstrate that knockout of the DNA base excision repair (BER) pathway, initiated by the DNA glycosylase NEIL1, is significantly more important than NER relative to the removal of the highly mutagenic AFB1-Fapy-dG adducts. Thus, our data suggest that deficiencies in NEIL1 could contribute to the initiation of HCCs in humans. To maximize relevance to human health, all known variants of NEIL1 will be characterized from regions of the world where aflatoxin ingestion and HBV infection are prevalent. All variants will be characterized for their biochemical properties relative to WT NEIL1 and expressed in cells and transgenic mice to understand the potential for catalytically- compromised variants of NEIL1 to alter susceptibility to aflatoxin exposures. These aims will test the hypothesis that expression of the oncogenic and other catalytically-compromised variants of NEIL1 can efficiently block repair and promote increased mutagenesis and carcinogenesis. Characterization of phenotypically dominant oncogenic variants of NEIL1 will provide the molecular basis from which to design human epidemiological studies in at-risk populations and early onset HCC cohorts. Further, this application proposes to establish the molecular mechanisms by which the combination of chronic inflammation driven by the hepatitis B surface antigen and deficiencies in DNA repair could synergistically drive AFB1-induced mutagenesis and carcinogenesis. Overall, these studies have direct human health relevance pertaining to understanding a global environmental health problem by identifying genetic risk factors and biochemical pathways previously not recognized as germane to AFB1-induced carcinogenesis.

行政补充资金申请摘要 长期饮食接触真菌毒素、黄曲霉毒素 B1 (AFB1) 和乙型肝炎病毒 (HBV) 的组合 感染与早发性肝细胞癌（HCC）风险显着增加相关 数百万人生活在东亚、中美洲、南美洲以及撒哈拉以南非洲。即使节食 接触黄曲霉毒素是导致癌症发生的第二大全球环境风险因素， 关于致癌的分子机制仍然存在重大问题。深入 了解这些机制对于识别影响个体的遗传风险因素至关重要 HBV 感染者和 AFB1 暴露者的易感性。在这方面，由于 AFB1 致癌作用是 由 G 到 T 颠换的高频诱变驱动，启动和修复 DNA 修复途径 完全修复 AFB1 诱导的持续性 DNA 加合物和 HBV 诱导的炎症造成的碱基损伤 具有很强的生物学意义。这些途径定义了靶组织中的诱变负荷， 最终限制细胞进展为癌症。尽管核苷酸切除修复（NER）途径已被 显示可以修复 AFB1 DNA 加合物，本文提供的小鼠数据表明 DNA 碱基的敲除 由 DNA 糖基化酶 NEIL1 启动的切除修复 (BER) 途径比 NER 涉及去除高度诱变的 AFB1-Fapy-dG 加合物。因此，我们的数据表明 NEIL1 的缺陷可能导致人类肝癌的发生。最大限度地提高与人类的相关性 为了健康，所有已知的 NEIL1 变体都将从世界上摄入黄曲霉毒素的地区进行鉴定 并且乙肝病毒感染很普遍。所有变体都将根据其相对于的生化特性进行表征 WT NEIL1 并在细胞和转基因小鼠中表达，以了解催化的潜力 NEIL1 的受损变体可改变对黄曲霉毒素暴露的敏感性。这些目标将考验 假设 NEIL1 的致癌变体和其他催化受损变体的表达可以 有效阻止修复并促进突变和致癌作用的增加。表征 NEIL1 的表型显性致癌变异将为设计提供分子基础 针对高危人群和早发性 HCC 人群的人类流行病学研究。此外，本申请 提出建立由以下因素驱动的慢性炎症组合的分子机制： 乙型肝炎表面抗原和 DNA 修复缺陷可以协同驱动 AFB1 诱导的 诱变和致癌作用。总体而言，这些研究与人类健康有直接相关性 通过识别遗传风险因素和生物化学来了解全球环境健康问题 以前不认为这些途径与 AFB1 诱导的致癌作用有密切关系。