Biofilm Epidemiology and Mechanisms in Colon Cancer

结肠癌生物膜流行病学和机制

基本信息

批准号：
9313210
负责人：
FRANCIS M GIARDIELLO
金额：
$ 86.84万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-07-08 至 2021-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9313210
关键词：
Adenomatous Polyps Affect African American Bacteria Cancer Etiology Carcinogenesis Mechanism Cell Proliferation Cessation of life Clinical Colon Colon Carcinoma Colonoscopy Colorectal Cancer Communities Complex DNA Sequence Alteration Data Detection Developed Countries Development Disease Distal Distant Distant Metastasis E-Cadherin Ecosystem Environment Environmental Exposure Epidemiology Epithelial Cells Excision Exhibits Foundations Frequencies Future Genes Genomic approach Genomics Geography Human Individual Interleukin-6 Lead Left Malignant - descriptor Malignant Neoplasms Measures Microbial Biofilms Microbiology Molecular Morbidity - disease rate Mucous Membrane Natural History Normal tissue morphology Oncogenic Operative Surgical Procedures Outcome Pathway interactions Population Population Control Prevention strategy Public Health Risk Sampling Signal Transduction Structure Testing Time Tissues United States Woman adenoma age group base burden of illness carcinogenesis carcinogenicity cell transformation cohort colon carcinogenesis colon hepatic flexure colorectal cancer prevention crypt cell follow-up human data improved outcome insight interest lifetime risk men microbial microbiota mortality novel preference prevent prospective test public health relevance screening structural biology structural genomics tool transcriptome sequencing tumor uptake

项目摘要

DESCRIPTION (provided by applicant): Colorectal cancer (CRC) is a public health threat in the United States. Because the colon contains the most densely populated microbial ecosystem known, there has been a longstanding interest in how environmental exposure of colonic epithelial cells to the microbiota contributes to the initiation and/or progression of human CRC. Our data accrued in CRC and healthy colonoscopy control populations reveal that combined approaches, structural microbiology and genomics, yield novel observations regarding the impact of the microbiota on the host colon mucosa. Namely, right (proximal) colon cancers (before the hepatic flexure) and their paired normal mucosal samples far distant from the CRCs are nearly universally covered by complex bacterial biofilms that exhibit bacterial invasion into all tumors and some normal colon tissues whereas left (distal) CRCs and normal tissues infrequently exhibit biofilms. In the healthy colonoscopy (non-tumor) host, only ~10-15% of colon tissues exhibit mucosal biofilms without geographic preference indicating the right colon is not natively associated with biofilm formation. Importantly, biofilm formation correlates with procarcinogenic pathway activation and crypt cell proliferation in tumor and non-tumor host colon tissues. Thus, we hypothesize that the proximal colon is susceptible to marked changes in bacterial organization that drive carcinogenesis. We will test our hypothesis using experimental approaches applied to a clinical colonoscopy cohort. Our specific aims are: 1) to establish the natural history of colon mucosal biofilm development; and 2) to define bacterial community and host mechanisms by which biofilms contribute to colon carcinogenesis. Our results will provide guidance to development of new tools for the prevention of CRC.

描述（由适用提供）：大肠癌（CRC）是美国的公共卫生威胁。由于结肠包含已知的最不庞大的微生物生态系统，因此人们对结肠上皮细胞环境暴露于微生物群如何促进人CRC的倡议和/或进展一直存在人们的兴趣。我们在CRC和健康结肠镜检查的人群中累积的数据表明，结合方法，结构微生物学和基因组学，对微生物群对宿主结肠粘膜的影响产生了新的观察结果。也就是说，右（近端）结肠癌（在肝柔韧性之前）和它们配对的正常粘膜样品与CRC相距甚远，几乎被复杂的细菌生物膜揭示，这些细菌将细菌侵入所有肿瘤侵入所有肿瘤和某些正常结肠组织中，而远离（远端）CRCS CRCS和正常的CRCS和非正常的组织无素质的无素质。在健康的结肠镜检查（非肿瘤）宿主中，只有约10-15％的结肠组织暴露于粘膜生物膜，没有地理偏好，表明右结肠与生物膜形成并非本地相关。重要的是，生物膜的形成与肿瘤和非肿瘤宿主结肠组织中的促炎途径的激活和隐窝细胞增殖相关。这就是我们假设，近端结肠容易受到驱动致癌的细菌组织的明显变化。我们将使用适用于临床结肠镜检查队列的实验方法检验假设。我们的具体目的是：1）建立结肠生物膜发展的自然历史； 2）定义细菌群落和宿主机制，生物膜有助于结肠癌发生。我们的结果将为开发预防CRC的新工具提供指导。