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Small molecule inhibitors for the study of colibactin-induced carcinogenesis by gut microbes

用于研究肠道微生物大肠杆菌素诱导癌变的小分子抑制剂

基本信息

批准号：
9907706
负责人：
Matthew Robert Volpe
金额：
$ 4.55万
依托单位：
HARVARD 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：
2020-02-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9907706
关键词：
Address Anabolism Animal Model Asparagine Bacteria Binding Biological Assay Biology Biopsy Boronic Acids Cancer Etiology Cell Cycle Arrest Cells Cellular Assay Cessation of life Chemicals Chemistry Chromosomal Instability Clinical Research Collaborations Colorectal Cancer Communities Complex Crystallization DNA DNA Adduction DNA Alkylation DNA Crosslinking DNA Crosslinking Agent DNA Double Strand Break Development Enzymes Epithelial Cells Escherichia coli Exposure to Fluorides Fluorogenic Substrate Future Gene Cluster Genetic Genomic Islands Health Human Human Microbiome Hydrolysis Hydrophobicity In Vitro Incidence Infection Institutes Ketones Knowledge Length Link Mammalian Cell Molecular Target Mus Mutagens Mutation Natural Products Organism Pathogenicity Pathway interactions Patients Peptide Hydrolases Peptides Positioning Attribute Prevention Process Production Proteome Reporting Research Risk Risk Factors Role Serine Structure Testing Therapeutic Therapeutic Intervention Time Tissues Toxin Tumor Burden Tumor Tissue United States Universities Work X-Ray Crystallography age group analog base carcinogenesis carcinogenicity cohort colorectal cancer prevention colorectal cancer progression colorectal cancer risk commensal microbes covalent bond crosslink design effectiveness testing gastrointestinal epithelium genotoxicity gut microbes gut microbiome gut microbiota high throughput screening in vivo inhibitor/antagonist member microbiome research microorganism molecular targeted therapies mortality mouse model novel novel strategies novel therapeutics pathogen periplasm prevent scaffold senescence small molecule small molecule inhibitor tissue culture tool tumor

项目摘要

PROJECT SUMMARY/ABSTRACT Colorectal cancer (CRC) is currently the second leading cause of cancer deaths in the United States and, as of 2018, shows an increasing mortality rate in younger age groups. The reason for this rise in mortality has not been fully explained and highlights the urgent need to better understand the causes and risk factors for CRC and develop novel strategies for its prevention and treatment. A growing body of evidence has implicated members of the human gut microbiome as potential drivers of CRC development. In particular, bacteria that produce a small molecule genotoxin known as colibactin may be key players in this process. Colibactin is produced by both commensal and pathogenic organisms which harbor the pks genomic island. Numerous studies have shown that transient infection of mammalian cells with pks+ E. coli leads to DNA crosslinking, DNA double-strand breaks, chromosomal instability, and senescence. Clinical studies have shown that pks+ bacteria are more prevalent in patients with CRC (~68%) and IBD (~40%) in comparison to healthy controls (21%) and are more abundant in tumor tissue biopsies than those from adjacent healthy tissue. In animal models, colonization with pks+ E. coli in a mouse model of CRC leads to increased tumor load relative to mice colonized with non-colibactin-producers. In perhaps the most direct evidence of colibactin’s carcinogenic potential, recent work has also shown that when mice are colonized with pks+ E. coli, colibactin directly alkylates DNA in gut epithelial cells, resulting in the formation of DNA adducts. Together, this evidence suggests that exposure to colibactin may increase risk for, or accelerate the development of, CRC via the mutagenic effects of DNA alkylation and crosslinking by colibactin. Despite this, no viable therapeutic strategy has emerged to prevent colibactin exposure, and no tools exist to study the effects of this pathway in the context of a complex, healthy gut-microbial community. This proposal aims to address these knowledge gaps by developing potent and specific small molecule inhibitors of colibactin biosynthesis. Such tool compounds will enable a more detailed study of how colibactin contributes to CRC progression and allow us to test the hypothesis that blocking colibactin production by pks+ bacteria using small molecules can lower the risk of developing CRC for the host. This research will both to explore a novel molecular target for therapeutic intervention in CRC development, as well as provide the wider scientific community with tools that will enable a more precise study of the impacts of small molecule toxins from commensal microbes on human health.

项目总结/文摘