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Sealing and healing of epithelial gaps

Link to faculty eProfessional résumé

Dr. Marshall Montrose

Professor COM Molecular & Cellular Physiology
College of Medicine
+1 (513) 558-5636

The intestinal epithelium presents a barrier to invasion of the body by undesirable luminal contents. Using both
immunohistochemistry and a new in vivo method for confocal and two-photon microscopy that allows study of
living villi, we find that the intestinal epithelium is punctuated by discontinuities caused by cell shedding and
potentially imperfect cell packing. Surprisingly, these cell-free gaps are filled with an impermeable substance
that maintains the epithelial barrier. Our results suggest that the epithelium can seal the epithelial barrier prior
to use of cell migration to heal gaps in the cell layer. While cell restitution will ultimately restore epithelial
continuity, our hypothesis is that the mechanism we have observed is the major defender of barrier function
immediately following villus cell shedding, and that perturbations of this mechanism lead to disease. Our goal
in this project is to address what we believe will be the fundamental points that will confirm or
deny the importance of our findings. We will
perform functional studies in normal and mutant mice using in vivo confocal and two-photon microscopy, and
use immunohistochemistry and confocal endoscopy for comparative studies between mouse and human
samples. In the first aim we will question the mechanisms that maintain barrier function during and after cell
shedding. Specifically, we will use enzymatic digestion, immunohistochemistry and micro-analytical tools to
define what class of material seals the gaps and sustains the epithelial barrier. We will also test if activation of
myosin light chain kinase mediates a purse string closure that heals gaps. In the second aim we will ask where
cells are lost and gaps are generated along a villus, using chimeric mice with a mosaic of crypt expression of
EGFP to measure the fate of the cohort of cells from an individual crypt that migrate onto a living villus. The
third aim is an initial confocal endoscopy study evaluating the characteristics, locale and frequency of epithelial
gaps in non-diseased human ileal tissue. The outcome of these studies will define molecules involved in
sealing and healing of gaps, and set the stage for us to define the importance of gaps in healthy and diseased
tissue (in particular diseases having altered intestinal permeability) in later work.

Project commenced on September 1, 2007

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Collaborative Institutions