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

基本信息

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
项目类别：
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

项目摘要

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.

行政补充资金请求的摘要慢性饮食暴露于真菌毒素，黄曲霉毒素B1（AFB1）和乙型肝炎病毒（HBV）的结合（HBV）感染与早期发作肝癌（HCC）的风险显着增加有关数百万居住在东亚，中美洲和南美以及撒哈拉以南非洲的人。即使饮食对黄曲霉毒素的暴露构成了癌症发展的第二大全球环境风险因素，关于驱动癌变的分子机制，仍然存在重大问题。深入对这些机制的了解对于鉴定影响个体的遗传风险因素至关重要对感染HBV的人的敏感性和暴露的AFB1。在这方面，由于AFB1癌变是由G到T横向的高频诱变驱动，T trypersions（启动和持续的AFB1诱导的DNA加合物和HBV诱导的炎症的基本损害的完全修复具有强大的生物学意义。这些途径定义了目标组织中的诱变负担最终将细胞进展限制为癌症。尽管核苷酸切除修复（NER）途径已经显示了用于修复AFB1 DNA加合物，此处介绍的鼠数据表明DNA碱基的敲除由DNA糖基酶Neil1发起的切除修复（BER）途径比相对于去除高度诱变的AFB1-FAPY-DG加合物的NER。因此，我们的数据表明 Neil1中的缺陷可能有助于人类的HCC启动。最大化与人的相关性健康，Neil1的所有已知变体将以世界各地的摄入量为特征 HBV感染很普遍。所有变体的生化特性相对于它们的生化特性都将被表征 wt neil1并在细胞和转基因小鼠中表达，以了解催化的潜力尼尔1的变体破坏了对黄曲霉毒素暴露的敏感性。这些目标将测试假设Neil1的致癌性和其他催化作用变体的表达有效阻止修复并促进诱变和致癌作用增加。表征尼尔1的表型主导的致癌变异将提供分子基础。人类的流行病学研究和早期发作HCC队列。此外，此应用程序提议建立分子机制，慢性炎症的组合由乙型肝炎表面抗原和DNA修复中的缺陷可以协同驱动AFB1诱导诱变和癌变。总体而言，这些研究具有与人类健康有关的直接相关性通过识别遗传危险因素和生化来了解全球环境健康问题以前未被认为是AFB1诱导的致癌作用的途径。