Role of Bacteria in Colitis-Associated Colon Cancer

摘要： 在上一个资助周期中，我们证明了特定的微生物活性对于 CRC的发展，例如在B2的某些大肠杆菌中存在致病性pks基因岛 组负责次级代谢物大肠杆菌素的合成（亚瑟，J.C.，等人（2012），Science 338（6103），120-123）。另外，我们最近观察到硫化氢的存在 在儿科人群中，产H2S细菌（HSPB）与新发克罗恩病（CD）的严重程度 （Mottawea，W.，等，2016. Nat Commun 7，1-14.）.我们的长期目标是确定细菌-宿主 相互作用影响结肠炎相关CRC的发展。当前竞争的目标 更新是为了确定宿主和环境因素如何调节细菌的致癌潜力。 该项目的中心假设是宿主来源的信号调节细菌产生的代谢产物 影响致癌作用。这项研究的基本原理是，一旦我们了解了这种相互作用， 在细菌和宿主之间，有可能针对特定的活动，从而发展结肠炎- 相关CRC。我们计划测试我们的中心假设，并实现本申请的总体目标， 具体目标。 目标1.定义Il 10-/-;Apcmin/+小鼠中细菌诱导的CRC所需的炎症要求。 目标二。在Il 10-/-;Apcmin/+小鼠中建立与细菌诱导的CRC有关的时间机制。 目标3。确定细胞类型特异性改变后的微生物应答和CRC发展， MYD 88信号转导的研究。 这些结果不仅可能为结直肠癌研究（炎症）开辟新的方向， 微生物功能的调节），而且还提供了新的靶标（组织特异性微生物感测和 微生物疾病促进活性）和用于治疗和 预防结肠直肠癌。

Summary: During the last funding cycle, we demonstrated that specific microbial activities are important for development of CRC, for example the presence of the pathogenic pks gene island, in certain E.coli of the B2 group, is responsible for the synthesis of the secondary metabolite colibactin (Arthur, J.C., et al. (2012), Science 338(6103), 120–123). In addition, we recently observed a correlation between the presence of hydrogen sulfide (H2S)-producing bacteria (HSPB) and the severity of new onset Crohn's disease (CD) in a pediatric population (Mottawea, W., et al, 2016. Nat Commun 7, 1–14.). Our long-term goal is to determine how bacteria-host interaction influences the development of colitis-associated CRC. The objective of the present competitive renewal is to determine how the host and environmental factors regulate the carcinogenic potential of bacteria. The central hypothesis of this project is that host-derived signaling modulates bacterial-generated metabolites to influence carcinogenesis. The rationale for the proposed research is that once we understand the interplay between bacteria and the host, it would be possible to target specific activity and thus development of colitis- associated CRC. We plan to test our central hypothesis and fulfill the overall objective of this application with the following specific aims. Aim 1. Define inflammatory requirement necessary for bacteria-induced CRC in Il10-/-;Apcmin/+ mice. Aim 2. Establish temporal mechanism implicated in bacteria-induced CRC in Il10-/-;Apcmin/+ mice. Aim 3. Determine microbial responses and CRC development following cell type-specific alteration of of MYD88 signaling in Il10-/- mice. The results will potentially not only open new directions of colorectal cancer research (inflammation modulation of microbial functions) but also provide novel targets (tissue-specific microbial sensing and microbial disease-promoting activity) and means (anti-inflammatory and anti-microbial agents) for treating and preventing colorectal cancer.