Microbial Metabolic Toxicity Drives Colon Cancer

微生物代谢毒性导致结肠癌

基本信息

批准号：
9079423
负责人：
Nicholas Chia
金额：
$ 38.83万
依托单位：
MAYO CLINIC ROCHESTER
依托单位国家：
美国
项目类别：
财政年份：
2014
资助国家：
美国
起止时间：
2014-06-05 至 2019-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9079423
关键词：
Antibiotics Archaea Attenuated Bacteria Biochemical Pathway Biopsy Biopsy Specimen Cancer Etiology Cells Cessation of life Characteristics Chronic Clinic Colon Colon Carcinoma Colonic Polyps Colonoscopy Colorectal Cancer Communities Consumption DNA DNA Damage DNA Sequence Alteration Data Set Diet Disease Distal Environmental Risk Factor Epithelial Epithelial Cells Equilibrium Exposure to Feces Gastrointestinal tract structure Genetic Genetic Models Genome Genomics Goals Health Hereditary Disease High Pressure Liquid Chromatography Human Hydrogen Sulfide Incidence Knowledge Lead Left Life Style Link Malignant Neoplasms Maps Measures Metabolic Metabolism Methanobacteria Methylation Microbe Mismatch Repair Modeling Mutagenesis Mutation Patients Phenotype Play Population Premalignant Probability Probiotics Production Psychological Techniques Resources Ribosomal RNA Risk Role Side Structure Techniques Technology Testing Tissue Sample Tissues Toxic effect Toxin adenoma base cancer risk cancer subtypes carcinogenesis colon carcinogenesis gastrointestinal gut microbiome metabolomics metagenome metagenomic sequencing microbial microbial community microbiome network models prebiotics reconstruction repository sulfate reducing bacteria targeted sequencing tumor

项目摘要

DESCRIPTION (provided by applicant): The proposed project will explore the hypothesis that chronic exposure to microbially-produced DNA damaging toxins such as hydrogen sulfide lead to an increased risk of colorectal cancer. According to this hypothesis, sulfate-reducing bacteria (SRBs) in colon can therefore lead to colon cancer unless their ability to generate hydrogen sulfide is attenuated by a competing metabolism such as methanogenesis. To test this, we will combine metabolic, regulatory, and evolutionary modeling with high throughput genomic technologies to explore the relationship between SRBs, methanogens, and the gastrointestinal microbial community in colorectal cancer and normal colonoscopy patients. We propose to conduct metagenome sequencing and assembly to study the possible interactions between the microbiome and hydrogen sulfide production based on the metabolic and regulatory networks of both microbes and tumors. If successful, we will have generated models that are capable of predicting the levels of various metabolite byproducts including toxic DNA damaging agents that impact the incidence of CRC and quantified the relationship between DNA damage and multiple subtypes of cancer.

描述（由申请人提供）：拟议项目将探讨以下假设：长期接触微生物产生的 DNA 损伤性毒素（如硫化氢）会导致结直肠癌风险增加。根据这一假设，结肠中的硫酸盐还原菌（SRB）可能导致结肠癌，除非它们产生硫化氢的能力被竞争性代谢（例如产甲烷作用）削弱。为了测试这一点，我们将代谢、调节和进化模型与高通量基因组技术相结合，探索结直肠癌和正常结肠镜检查患者中SRB、产甲烷菌和胃肠道微生物群落之间的关系。我们建议进行宏基因组测序和组装，以基于微生物和肿瘤的代谢和调节网络来研究微生物组和硫化氢产生之间可能的相互作用。如果成功，我们将生成能够预测各种代谢副产物（包括影响 CRC 发病率的有毒 DNA 损伤剂）水平的模型，并量化 DNA 损伤与多种癌症亚型之间的关系。