Deciphering the Role of Gut Microbiome in Inflammatory Bowel Disease Using a Canine Patient-Specific Gut-on-a-Chip

PROJECT SUMMARY
This NIH ORIP K01 award application describes a 5-year training plan designed to allow me to gain additional
skill and knowledge so that I can transition to an independent R01-funded tenure track research scientist. In
carrying out the proposed research and career development plan, I will add to my scientific repertoire and acquire
expertise in intestinal stem cell biology, microbiome, and microfluidic organ-on-chip technology. Using this newly
acquired expertise, I will establish a scientific niche that will set me apart from my mentors and pave the way to
a robust, extramurally funded research program. With the support of my mentoring team, I have designed a
robust research program that leverages my extensive expertise with comparative gastroenterology and
molecular biology. Specifically, Aim 1 will demonstrate molecular and genetic alterations affecting canine IBD
following the development and validation of a patient-specific IBD model that can quantitatively assess the
cellular and molecular signature of host-microbiome crosstalk. Aim 2. will allow mapping of the microbial
signature and epithelial integrity in response to the host-microbiome intercellular crosstalk by utilizing single-cell
level multi-omics (especially genomics and transcriptomics) and RNA in situ hybridization. Consistent with the
ORIP’s mission statements promoting veterinary scientists to employ their expertise in comparative medicine to
investigate human diseases, my research will allow me to use my expertise in comparative gastroenterology as
well as in primary stem cell culture to investigate alterations in intestinal homeostasis relevant to Inflammatory
Bowel Disease. Also, as ORIP supports animal modeling of human diseases, I will be using the dog as a
spontaneous animal model to investigate the effect of gut microbiota in the intestinal epithelium given their
genetic and physiological similarity to humans. The results generated in this proposal have direct implications
for human diseases, since they will provide new insights into genetic and transcriptomic alterations initiating or
maintaining the chronic inflammation in the gut. Such findings can be applied to various chronic conditions that
have been epidemiologically associated with microbiome dysbiosis and disturbances of intestinal health (i.e.,
Colorectal Cancer, Diabetes Mellitus, and Alzheimer’s Disease, to name a few). This knowledge may be applied
to understand disease development and novel therapies aimed at modifying intestinal homeostasis via
perturbation of epithelium-microbiome-immune axis in the intestine. In summary, the training goals and career
development activities proposed in this application will promote my successful transition into independent
research directions.

Grant Number: 5K01OD030515-05
NIH Institute/Center: NIH
Principal Investigator: Yoko Ambrosini