Patients with inflammatory bowel diseases (IBD) experience an increased risk of inflammation-associated colorectal cancer (I-CRC), mediated through the effects of the inflammatory environment on both the host and the microbiota. However, it remains unclear how inflammation impacts the composition of the colonic-adherent microbiota over time, the functional capabilities of inflammation-associated microbes, and how these capabilities augment inflammation and I-CRC. My research interests focus upon understanding how the IBD microenvironment alters the pro-inflammatory and pro-carcinogenic capabilities of the microbiota with the goal of targeting these microbes as a therapeutic strategy to lessen inflammation and reduce the risk of I-CRC. My immediate goals are to establish an independent area of basic and translational research that is distinct from my mentors, clinically relevant, and likely to attract continuous funding. I will accomplish these goals with the followin training objectives: (I) develop the necessary skills and expertise to mechanistically evaluate the relationship between the microbiota and its effects on intestinal inflammation and I-CRC, and (II) generate innovative data to publish in high quality peer-reviewed journals and obtain independent funding. Attaining these goals will allow me to reach my long-term career goal, to lead a team of multidisciplinary scientists and succeed as an independently funded academic investigator pursuing innovative digestive diseases research. The scientific objective of the current proposal is to define inflammation-induced alterations to the mucosally- adherent microbiota and demonstrate the cancer-promoting impact of inflammation-associated genotoxic Enterobacteriaceae. Increased mucosally-adherent bacteria, particularly Enterobacteriaceae, are observed in IBD patients and mouse models. This positions these bacteria at an ideal location in which to interact with host epithelial cells and exert pro-inflammatory and pro-carcinogenic activities. We hypothesize that inflammation supports the expansion of genotoxic Enterobacteriaceae at the colonic mucosa and this augments I-CRC through increased DNA damage. We will test this hypothesis in two Specific Aims.
In Aim 1, we will define the impact of inflammation on the composition of the colonic-adherent microbiota over time in Interleukin-10- deficient (Il10-/-) mice.
In Aim 2, we will isolate, characterize and test the cancer-promoting activity of colonic- adherent, inflammation-associated, genotoxic Enterobacteriaceae using modern sequencing technology and gnotobiotic I-CRC mouse models. The environment at UNC Chapel Hill houses two unique cores that are essential for these studies: the High Throughput Sequencing Core and the NIH-funded National Gnotobiotic Rodent Resource Center. Demonstrating a cancer-promoting effect of inflammation-associated genotoxic bacteria and identifying specific microbes and microbial pathways that promote I-CRC will reveal novel targets that may be predictive of an elevated risk for I-CRC in IBD patients and help target novel selective therapies.

Public Health Relevance

Patients with longstanding inflammatory bowel diseases (IBD), including Crohn's disease and ulcerative colitis, are at a higher risk for developing colorectal cancer (CRC). Current treatments are often ineffective. Although the exact cause is unknown, intestinal bacteria are strongly implicated in these diseases. The studies in this proposal will evaluate the impact of inflammation on the community of intestinal bacteria and their ability to promote inflammation-associated CRC (I-CRC). Demonstrating a cancer-promoting effect of inflammation- associated bacteria and identifying specific bacteria and bacterial pathways that promote I-CRC will reveal novel targets for the diagnosis and treatment of I-CRC.

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Research Scientist Development Award - Research & Training (K01)
Project #
1K01DK103952-01
Application #
8805196
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Podskalny, Judith M,
Project Start
2014-09-17
Project End
2019-08-31
Budget Start
2014-09-17
Budget End
2015-08-31
Support Year
1
Fiscal Year
2014
Total Cost
$151,681
Indirect Cost
$11,236
Name
University of North Carolina Chapel Hill
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
608195277
City
Chapel Hill
State
NC
Country
United States
Zip Code
27599