Microbial Induction of Colon Cancer and Mechanisms (PQ12)

描述(申请人提供)：散发性结直肠癌(CRC)是美国男性和女性的第二大死亡原因，因此是一个主要的公共卫生问题，现有的预防措施目前尚不健全。感染和炎症过程在结肠癌发生中的作用是人们非常感兴趣的，因为结肠中有~1012-13个共生菌，如果结肠上皮的动态平衡被破坏，就有可能诱导炎症过程。在这里，我们寻求支持来检验这一假设，即人类CRC与一个致癌微生物区系有关，该微生物区系诱导了直接影响肿瘤发展的特定的癌前免疫和代谢途径。我们认为，特定的微生物区系、代谢和/或免疫学机制将为检测和预防结直肠癌提供新的基础。该项目代表了约翰霍普金斯大学(西尔斯)、J·克雷格·文特尔研究所(JCVI，Peterson)和斯克里普斯研究所(Siuzdak)三个主要研究人员和机构的联盟，以利用约翰霍普金斯大学强大的人类样本积累计划结合微生物组(JCVI)和新陈代谢组(Scripps)的专业知识来解决我们的假设。通过我们的具体目标，我们将确定与结直肠癌相关的微生物种群，定义人类结直肠癌的元基因组组成，并定义早期代谢物以及微生物组和结直肠癌之间的生化关联(S)。将应用生物信息学方法并与临床数据相结合，以确定与结直肠癌相关的候选微生物、免疫学和/或代谢生物标记物。结直肠癌生物标志物的识别有可能应用于结直肠癌的早期发现，以及通过疫苗接种和/或通过饮食、益生菌给药或药物进行代谢调节等方法，为高危个体制定干预措施。 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费用和不便而未得到充分利用，从而导致过高的发病率和死亡率。该项目将整合微生物区系、免疫学和代谢学数据，以确定具有加强人类结肠癌预防和检测潜力的新生物标记物。

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.