Dr. James Lillich
Dr. James LillichAssociate Professor
Department of Clinical Sciences
Phone: (785) 532-5700
e-mail: lillich@vet.k-state.edu
Mentor : Dr. Lisa Freeman
Intestinal Epithelial Wound Healing: NSAIDs and Calpain
Inhibition:
Non-steroidal anti-inflammatory drugs (NSAIDs) are among the most
widely used medications worldwide despite their well-documented
gastrointestinal (GI) toxicity. The GI epithelium has several
functions, the most important of which are nutrient absorption and
barrier function, separating the internal milieu from the external
environment. Mucosal restitution represents a primary repair
modality in the GI tract, and allows resealing of the epithelial
barrier in minutes to hours via reformation of tight junctions
between cells. Restitution requires cell migration, but not cell
proliferation nor differentiation and it is a well coordinated event
relying on numerous cellular pathways. Recent evidence suggests that
calpains (cysteine proteases) are vital to several key pathways of
cell migration. Recently we have shown that: a) irrespective of COX
selectivity, ulcerogenic NSAIDs inhibit cell migration after
wounding; b) individual NSAIDs differ significantly in their effects
on the cellular signals that modulate cell migration; and c)
ulcerogenic NSAIDs either down-regulate calpain gene expression or
up-regulate the constituent inhibitor, calpastatin. Project experiments are specifically designed to link NSAID
inhibition of cell migration with NSAID effects on events vital to
calpain function within differentiated intestinal epithelial cells
(IECs).
- The specific aims of this project are to:
- Demonstrate that calpains are critical to normal IEC migration.
- Confirm that calpains are a target for NSAID-toxicity and disruption of intestinal epithelial wound healing.
- Determine the effects of NSAIDs on calpain-mediated adhesion dynamics.