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：
8303450
负责人：
DREW M. PARDOLL
金额：
$ 57.03万
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/8303450
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）：我们已经鉴定出一种人类结肠厌氧细菌，产肠毒素脆弱拟杆菌（ETBF），作为结肠癌的候选病原体，并且我们的 ETBF 定植小鼠模型描绘了 ETBF 诱导的潜在致癌免疫途径。正如幽门螺杆菌的发现改变了人们对消化性溃疡病和随之而来的胃癌的认识一样，我们推测 ETBF 通过分泌强效脆弱拟杆菌毒素 (BFT)，引发致癌粘膜免疫反应，从而促进结肠形成癌症。我们的模型并不打算改变结肠癌现有的突变范式，而是提出 ETBF 定植是解释结肠癌发生所需的基因突变积累的一个完整机制。该提案将研究人类中 ETBF 的结肠定植、特定结肠免疫反应以及最终结肠癌之间的关系。定义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，是美国女性和男性癌症死亡的第二大原因。所研究的任何两个变量（ETBF 定植、结肠免疫反应和结肠癌）之间的显着相关性将实质性改变当前结肠癌发病机制、预防和治疗的范例。公共卫生相关性：结肠癌是女性和男性癌症死亡的第二大原因。目前预防结肠癌的方法由于费用昂贵且不方便而繁琐且未得到充分利用。该项目提出，结肠癌是由一种称为产肠毒素脆弱拟杆菌 (ETBF) 的常见粪便细菌引发的，并将测试 ETBF 的检测和/或对 ETBF 的结肠免疫反应是否提供新的、更简单的方法来预防由于肠道毒素引起的发病率和死亡率。到结肠癌。