We are broadly interested in the process intestinal epithelial cell specification. This process begins with stem cells that reside in the crypts of Lieberkuhn, where active cell division occurs. The progenies of the stem cell migrates up the intestinal gland, during which they will encounter different environments and receive instructive cues to undergo differentiation programs to become one of the six functional intestinal cell lineages. This process ends with cell shedding at the villous tips. Although individual pathways have been identified to affect this process, cells in physiological settings are simultaneously exposed to multiple factors resulting in changes in multiple pathways. How cells integrate multivariate information to make cell decisions is currently unknown, especially in the context of diseases.
We utilize two technologies: highly multiplexable immunofluorescent microscopy (MxIF) and mass cytometry (CyTOF), to generate quantitative signaling datasets amenable to mathematical modeling. Both of these technologies can quantitate the levels of ~60 proteins at single cell resolutions. These methods have their strengths and drawbacks. For example, MxIF maintains localization information while CyTOF is capable of sampling the whole tissue. These techniques are complementary and necessary to obtain rich datasets for data-driven modeling. We use mechanistic models to describe and predict functional interactions between measured pathways at the molecular level, while we use statistical modeling to integrate changes over time and space to arrive at phenotypic outcomes.
We are applying our approach to study how the aberrant extracellular environment alters the multi-pathway network in two intestinal diseases: inflammatory bowel disease and colorectal cancer.
We hope that by obtaining a single cell - systems level understanding of the mechanism of pathological processes in diseases, we will devise better and more personalized therapies for these complex conditions.