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，因此是一个主要的公共卫生问题，目前可用的预防措施摇摇欲坠。感染和炎症过程在结肠癌发生中的作用引起了人们的强烈兴趣，因为结肠定植有1012-13个共生细菌，如果结肠上皮稳态被破坏，这些共生细菌有可能诱导炎症过程。在此，我们寻求支持来验证人类结直肠癌与致癌微生物群相关的假设，这些微生物群诱导特异性的致癌前免疫和代谢途径，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。该项目由约翰霍普金斯大学（Sears）、J. Craig Venter研究所（JCVI, Peterson）和斯克里普斯研究所（Siuzdak）三个主要研究机构组成，通过约翰霍普金斯大学结合微生物组（JCVI）和代谢组（Scripps）专业知识的强大的人类样本累积程序来解决我们的假设。通过我们的具体目标，我们将确定与CRC相关的微生物种群，确定人类CRC的宏基因组组成，确定早期代谢物以及微生物组与CRC之间的生化关联。生物信息学方法将被应用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、免疫和/或代谢生物标志物。结直肠癌生物标志物的鉴定有可能应用于结直肠癌的早期检测，以及通过接种疫苗和/或通过饮食、益生菌管理或药物调节代谢等方法对高危个体进行干预。

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.