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Enterotoxigenic Bacteroides fragilis: A bacterial promoter of colon oncogenesis

产肠毒素脆弱拟杆菌：结肠癌发生的细菌启动子

基本信息

批准号：
8137121
负责人：
DREW M. PARDOLL
金额：
$ 52.15万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-09-02 至 2015-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8137121
关键词：
Accounting Acute Affect Age Anaerobic Bacteria Animal Model Bacteria Bacteroides fragilis Cancer Control Cancer Etiology Cancer Patient Cells Cessation of life Chronic Clinical Colitis Colon Colon Carcinoma Colonic Neoplasms Crohn&apos s disease DNA Damage Dendritic Cells Detection Development E-Cadherin Epithelial Etiology Exposure to Feces Figs - dietary Funding Gene Mutation Genes Helicobacter pylori Homeostasis Human Immune Immune response Immune system Incidence Indium Inflammatory Inflammatory Bowel Diseases Interleukin-17 Lead Malignant Neoplasms Metalloproteases Modeling Morbidity - disease rate Mucosal Immune Responses Mus Mutant Strains Mice Nested Case-Control Study Oncogenic Pathogenesis Pathway interactions Patients Peptic Ulcer Prevention approach Prevention therapy Production Public Health Race Research Design Serologic tests Signal Transduction Solid T-Lymphocyte Subsets Testing Time Toxin Tumor Suppressor Proteins Ulcerative Colitis United States Woman base c-myc Genes carcinogenesis colon carcinogenesis experience malignant stomach neoplasm men microbial mortality novel diagnostics novel therapeutics pathogen promoter protein E public health relevance repository response sensor sex socioeconomics tumor tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): We have identified a human colon anaerobic bacterium, enterotoxigenic Bacteroides fragilis (ETBF), as a candidate etiologic agent for colon cancer and our murine models of ETBF colonization delineate a potential procarcinogenic immune pathway that ETBF induce. Just as the understanding of peptic ulcer disease and ensuing stomach cancer was transformed by the discovery of H. pylori, we hypothesize that ETBF, by secreting the potent B. fragilis toxin (BFT), precipitate procarcinogenic mucosal immune responses, thereby promoting formation of colon cancer. Our model does not propose to alter existing mutational paradigms of colon cancer but rather proposes that ETBF colonization is an integral mechanism accounting for the accumulation of genetic mutations necessary for colon carcinogenesis. This proposal will study the relationship between colon colonization by ETBF in humans, specific colon immune responses and, ultimately, colon cancer. Defining a microbial etiology for colon cancer has key implications as colon cancer is a major public health problem being the second leading cause of cancer death in the United States in women and men. A significant correlation between any two of the studied variables - ETBF colonization, colon immune responses and colon cancer -- will substantively alter current paradigms for the pathogenesis, prevention and therapy of colon cancer. PUBLIC HEALTH RELEVANCE: Colon cancer is the second leading cause of cancer death for women and men. Current approaches to prevention of colon cancer are cumbersome and underutilized due to their expense and inconvenience. This project proposes that colon cancer is triggered by a common stool bacterium called enterotoxigenic Bacteroides fragilis (ETBF) and will test whether detection of ETBF and/or the colon immune response to ETBF provide new, easier approaches to the prevention of the morbidity and mortality due to colon cancer.

描述（由申请人提供）：我们已经确定了一种人类结肠厌氧细菌，产肠毒素的脆弱拟杆菌（ETBF），作为结肠癌的候选病原，我们的ETBF定植的小鼠模型描绘了ETBF诱导的潜在的致癌前免疫途径。正如幽门螺杆菌的发现改变了对消化性溃疡疾病和随之而来的胃癌的认识一样，我们假设ETBF通过分泌强效的脆弱杆菌毒素（BFT），沉淀癌前黏膜免疫反应，从而促进结肠癌的形成。我们的模型并不建议改变现有的结肠癌突变模式，而是提出ETBF定殖是结肠癌发生所需的基因突变积累的完整机制。该提案将研究ETBF在人类结肠定殖，特定结肠免疫反应和最终结肠癌之间的关系。确定结肠癌的微生物病因具有重要意义，因为结肠癌是一个主要的公共卫生问题，是美国男性和女性癌症死亡的第二大原因。任何两个研究变量（ETBF定植、结肠免疫反应和结肠癌）之间的显著相关性将实质性地改变目前结肠癌发病机制、预防和治疗的范式。