Microbial Induction of Colon Cancer and Mechanisms (PQ12)

描述（由申请人提供）：散发性结直肠癌（CRC）是美国男性和女性死亡的第二大原因，因此是目前可用预防措施不稳定的主要公共卫生问题。感染性和炎症过程在结肠癌发生中的作用是非常令人感兴趣的，因为结肠中定植有约1012-13种肠道细菌，如果结肠上皮稳态被破坏，则可能诱导炎症过程。在此，我们寻求支持，以测试假设，即人类CRC与致癌微生物群，诱导特定的前致癌免疫和代谢途径，直接影响肿瘤的发展。我们认为，特定的微生物群、代谢和/或免疫机制将为CRC的检测和预防提供新的基础。该项目代表了三个主要研究者和机构，约翰霍普金斯（西尔斯），J.克雷格文特尔研究所（JCVI，彼得森）和斯克里普斯研究所（Siuzdak）之间的联盟，以解决我们的假设，使用约翰霍普金斯强大的人类样本积累计划结合微生物组（JCVI）和代谢组（斯克里普斯）的专业知识。通过我们的具体目标，我们将确定与CRC相关的微生物种群，定义人类CRC的宏基因组组成，并定义早期代谢物和微生物组与CRC之间的生化关联。将应用生物信息学方法并与临床数据相结合，以确定与CRC相关的候选微生物，免疫学和/或代谢生物标志物。CRC生物标志物的鉴定具有应用于CRC的早期检测以及通过诸如疫苗接种和/或经由饮食、益生菌施用或药物的代谢调节的方法开发针对高风险个体的干预的潜力。 公共卫生相关性：结肠癌是美国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其费用和不便而未得到充分利用，导致过高的发病率和死亡率。该项目将整合微生物群，免疫学和代谢组学数据，以确定有潜力加强预防和检测人类结肠癌的新型生物标志物。

DESCRIPTION (provided by applicant): Sporadic colorectal cancer (CRC) is the second leading cause of death for men and women in the United States and, hence, is a major public health problem for which available preventive measures currently falter. The role of infectious and inflammatory processes in colon carcinogenesis is of intense interest since the colon is colonized with ~1012-13 commensal bacteria with the potential to induce inflammatory processes if colonic epithelial homeostasis is disrupted. Herein, we seek support to test the hypothesis that human CRC is associated with an oncogenic microbiota that induces specific procarcinogenic immune and metabolic pathways that directly affect tumor development. We propose that specific microbiota, metabolic and/or immunologic mechanisms will provide a new basis for detection and prevention of CRC. This project represents a consortium among three principal investigators and institutions, Johns Hopkins (Sears), J. Craig Venter Institute (JCVI, Peterson) and the Scripps Institute (Siuzdak) to address our hypothesis using a robust human sample accrual program at Johns Hopkins combined with microbiome (JCVI) and metabolome (Scripps) expertise. Through our specific aims, we will identify the microbial populations associated with CRC, define the metagenomic composition of human CRC and define early metabolites and the biochemical association(s) between the microbiome and CRC. Bioinformatic approaches will be applied and integrated with clinical data to identify candidate microbial, immunologic and/or metabolic biomarkers associated with CRC. Identification of CRC biomarkers has the potential for application to the early detection of CRC as well as to development of interventions for high risk individuals through approaches such as vaccination and/or metabolic regulation via diet, probiotic administration or drugs. PUBLIC HEALTH RELEVANCE: Colon cancer is the second leading cause of cancer death for women and men in the United States. Current approaches to prevention of colon cancer are underutilized due to their expense and inconvenience leading to excessive morbidity and mortality. This project will integrate microbiota, immunologic and metabolomic data to identify novel biomarkers with potential to enhance the prevention and detection of human colon cancer.