Understanding the Mechanism of a Gut Microbial Genotoxin Involved in Colorectal Carcinogenesis

了解肠道微生物基因毒素参与结直肠癌发生的机制

• 批准号: 9174570
• 负责人: Emily Patricia Balskus
• 金额: $ 39.82万
• 依托单位: HARVARD UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9174570
• 关键词: Affect; American; Anabolism; Animal Model; Bacteria; Biology; Cancer Etiology; Cell Line; Cells; Cellular biology; Cessation of life; Chemical Structure; Chemicals; Chromosomal Instability; Colitis; Collaborations; Colorectal Cancer; DNA; DNA Adducts; DNA Damage; DNA Double Strand Break; Development; Diagnosis; Disease; Engineering; Enzymatic Biochemistry; Escherichia coli; Eukaryotic Cell; Future; Gene Cluster; Goals; Human; In Vitro; Incidence; Individual; Infection; Inflammatory Bowel Diseases; Investigation; Island; Knowledge; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Methodology; Methods; Microbiology; Molecular; Mus; Mutagens; Natural Products; Organic Chemistry; Outcome; Pathway interactions; Patients; Peptide Hydrolases; Production; Public Health; Research; Role; Structure; Techniques; Testing; Therapeutic Intervention; Toxicology; United States; Woman; Work; abstracting; cancer initiation; cancer prevention; cancer type; carcinogenesis; colon carcinogenesis; design; genotoxicity; gut microbiota; high throughput screening; in vivo; in vivo Model; inhibitor/antagonist; insight; interdisciplinary approach; men; microbial; microbiome; microbiota; microorganism; mouse model; prevent; programs; response; small molecule; tool; tumor progression; tumorigenesis

Project Summary / Abstract Colorectal cancer (CRC) is the third most prevalent form of cancer in the US and the second leading cause of cancer deaths, with an estimated 50,000 Americans succumbing to CRC in 2015. Studies over the last several decades have revealed that the gut microbiota influences multiple types of cancer, including CRC, and recent work has implicated bacterial genotoxins as key effectors in cancer development and progression. One of the bacterial genotoxins most strongly connected to cancer is colibactin, a metabolite produced by human gut commensal E. coli strains that possess a biosynthetic gene cluster dubbed the pks island. The increased abundance of pks+ E. coli found in CRC and inflammatory bowel disease (IBD) patients and the ability of pks+ strains to potentiate tumorigenesis in mouse models of CRC suggests that colibactin may promote cancer progression. However, achieving a mechanistic understanding of colibactin-mediated DNA damage and genotoxicity has been impeded by an inability to isolate this metabolite or otherwise assign its chemical structure. The overall objective of this proposal is to uncover the molecular mechanism underlying colibactin's genotoxic activity in order to understand and prevent colibactin-mediated carcinogenesis. Preliminary results have revealed that the colibactin biosynthetic pathway assembles structural features found in other DNA- damaging natural products, leading to the hypothesis that colibactin's genotoxicity arises from a direct interaction with DNA. To test this idea and obtain critical knowledge needed to ascertain colibactin's impact on CRC, our three complementary specific aims are to: 1) elucidate the chemical structure of colibactin by integrating multiple isolation strategies; 2) decipher the mechanism by which colibactin exposure leads to DNA damage; and 3) identify small molecules that inhibit colibactin biosynthesis. These advances will be enabled by our multidisciplinary approach, which merges knowledge and techniques from organic chemistry, chemical biology, biosynthesis and enzymology, microbiology, toxicology, and human cell biology. Overall, this effort will generate the tools and knowledge needed to elucidate the role of colibactin-producing bacteria in CRC initiation and progression in humans. By successfully demonstrating that studying and manipulating individual disease-associated microbial metabolic pathways can provide key mechanistic insights, this work will support and validate our future efforts to understand how other gut microbial metabolic activities influence CRC initiation and development.

项目摘要 /摘要 结直肠癌（CRC）是美国第三大流行的癌症形式，也是第二个主要原因 癌症死亡，估计有50,000名美国人在2015年屈服于CRC。 几十年来揭示了肠道微生物群会影响多种类型的癌症，包括CRC，最近 工作已将细菌基因毒素视为癌症发展和进展的关键效应因子。中的一个 与癌症最密切相关的细菌基因毒素是结肠癌，它是人肠产生的代谢产物 具有生物合成基因簇的共生大肠杆菌菌株称为PKS岛。增加 在CRC和炎症性肠病（IBD）患者中发现的PK+大肠杆菌的丰度以及PKS+的能力 在CRC小鼠模型中增强肿瘤发生的菌株表明Colibactin可能促进癌症 进展。但是，对Colibactin介导的DNA损伤和 遗传毒性阻碍了这种代谢物或以其他方式分配其化学物质的阻碍 结构。该提议的总体目的是揭示出色的结肠癌的分子机制 遗传毒性活性是为了理解和预防结肠癌介导的癌变。初步结果 已经揭示了共乳糖素生物合成途径的组装在其他DNA中发现的结构特征 损害天然产物，导致了下肠痛的遗传毒性的假设是由直接产生的 与DNA相互作用。测试这一想法并获得确定科里巴辛对影响的关键知识 CRC，我们的三个补充特定目的是：1）通过 整合多种隔离策略； 2）破译结肠癌导致DNA的机制 损害; 3）鉴定抑制colibactin生物合成的小分子。这些进步将由 我们的多学科方法，该方法合并了有机化学的知识和技术 生物学，生物合成和酶学，微生物学，毒理学和人类细胞生物学。总的来说，这项努力将 生成阐明产生结肠蛋白细菌在CRC中的作用所需的工具和知识 人类的启蒙和进步。通过成功证明研究和操纵个人 与疾病相关的微生物代谢途径可以提供关键的机械见解，这项工作将支持 并验证我们未来的努力，以了解其他肠道微生物代谢活动如何影响CRC 启动与发展。