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：
10320374
负责人：
Matthew Robert Volpe
金额：
$ 1.62万
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 2022-06-10
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10320374
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 member microbiome research microorganism molecular targeted therapies mortality mouse model novel novel strategies novel therapeutics pathogen periplasm prevent rational design 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.

项目概要/摘要结直肠癌（CRC）目前是美国第二大癌症死亡原因截至 2018 年，年轻群体的死亡率不断上升这是死亡率上升的原因。尚未得到充分解释，并强调迫切需要更好地了解其原因和风险因素越来越多的证据表明结直肠癌并制定新的预防和治疗策略。人类肠道微生物组的成员是结直肠癌发展的潜在驱动因素，特别是细菌。产生一种称为大肠杆菌素的小分子基因毒素可能是这一过程的关键参与者。由含有大量 pks 基因组岛的共生生物和病原生物产生。研究表明，pks+ 大肠杆菌短暂感染哺乳动物细胞会导致 DNA 交联， DNA 双链断裂、染色体不稳定和衰老临床研究表明 pks+。与健康对照者相比，细菌在 CRC (~68%) 和 IBD (~40%) 患者中更为普遍 (21%)，并且在肿瘤组织活检中比来自动物的邻近健康组织更丰富。模型中，pks+ 大肠杆菌在 CRC 小鼠模型中的定植导致肿瘤负荷相对于小鼠增加与非大肠杆菌素生产者定植，这也许是大肠杆菌素致癌的最直接证据。潜力，最近的工作还表明，当小鼠被 pks+ 大肠杆菌定植时，大肠杆菌素直接烷基化肠道上皮细胞中的 DNA，导致 DNA 加合物的形成。表明接触大肠杆菌素可能会通过以下途径增加结直肠癌的风险或加速结直肠癌的发展：尽管如此，仍没有可行的治疗策略。已经出现了防止大肠杆菌素暴露的工具，并且没有工具来研究该途径在体内的影响该提案旨在解决这些知识差距。通过开发大肠杆菌素生物合成的有效且特异性的小分子抑制剂。将使我们能够更详细地研究大肠杆菌素如何促进结直肠癌进展，并允许我们测试假设使用小分子阻断 pks+ 细菌产生大肠杆菌素可以降低感染的风险这项研究将探索一种新的治疗分子靶标。干预 CRC 的发展，并为更广泛的科学界提供工具，使更精确地研究共生微生物的小分子毒素对人类健康的影响。