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.
Numerous evidence links the microbiota to susceptibility to developing colitis and colorectal cancer in preclinical models. However, little is known regarding the interaction between host-derived signaling and carcinogenic potential of the microbiota. This project investigates how specific microbial functions are influenced by host genetics and environmental stressors, such as inflammation, to modulate colorectal cancer development.
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