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Research Interests

 

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Understanding the Barrier

Structure of the intestinal epithelium.

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The epithelial lining of the gastrointestinal tract serves as a dynamic and selective barrier permitting uptake of luminal nutrients while restricting pathogen and toxin access to underlying tissue compartments. Epithelial cells provide a unique interface between the luminal environment and immune cells in the sub-epithelial space or lamina propria. Barrier properties are achieved by intercellular junction proteins residing in a series of cell – cell contacts that include tight and adherens junctions as well as desmosomes. These specialized cell-cell contacts consist of over 100 proteins that actively participate in the complex process of controlling barrier function and epithelial homeostasis. We are interested in identifying and functionally characterizing these protein constituents of intercellular junctions. 


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Defending the Barrier

Pathophysiology of barrier compromise.

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Many acute and chronic inflammatory conditions result in compromised epithelial barrier function with enhanced permeability and increased exposure of mucosal immune cells to microbial antigens. Under these conditions, there is release of cytokines and chemokines that act to further perturb epithelial barrier function. Breakdown of the epithelial barrier has been shown to play a key role in the pathogenesis of several chronic inflammatory disorders of the intestine collectively referred to as Inflammatory Bowel Disease (IBD). Our studies are aimed at identifying molecular mechanisms by which such immune mediators control intercellular junction protein dynamics and epithelial barrier function. The ultimate objective is to develop strategies to strengthen the epithelial barrier and restore mucosal homeostasis under pathologic conditions.


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Mobilizing Defenders of the Barrier

Leukocyte trafficking in mucosal inflammatory disease.

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A major component of many inflammatory diseases of the gastrointestinal, respiratory, and urinary tract is migration of large numbers of leukocytes termed neutrophils (PMN) across the epithelium. While a necessary component of the inflammatory response against invading pathogens, pathologic PMN transmigration also commonly occurs in response to unknown stimuli in a number of diseases such as IBD.  Under these conditions, disease symptoms are directly related to leukocyte effects on the epithelial barrier and epithelial cell function. Conversely, it is now appreciated that epithelial mucosal homeostasis is highly dependent upon relationships between the epithelial barrier and leukocytes,  regulated, in part, by cell- cell contact and release of factors that initiate subsequent signaling events. While much has been learned about mechanisms of leukocyte migration from the circulation, relatively little is known about the receptors that regulate leukocyte-epithelial interactions. We are interested in understanding the structure and function of leukocyte (PMN) and epithelial receptors that mediate leukocyte transepithelial migration, and understanding the molecular basis and functional consequences of leukocyte-epithelial crosstalk. Importantly, identification and characterization of proteins that mediate leukocyte-epithelial interactions will provide new strategies for mucosal targeted therapeutics with a potential benefit of less systemic side effects than conventional therapies for conditions such as Inflammatory Bowel Disease.


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Rebuilding the Barrier

Molecular mechanisms of epithelial repair.

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Mucosal wounds and barrier disruption are characteristic of multiple clinical conditions that include inflammatory diseases (secondary to infection or idiopathic as in IBD), compromised circulation, irradiation and following surgical procedures. Epithelial wound closure involves concerted integration of epithelial cell proliferation and migration and requires a complex network of epithelial receptors (G-protein coupled receptors such as Formyl peptide receptors) and signaling events derived from pro-resolving mediators released by epithelial cells, leukocytes and luminal microbiota.  We are interested in elucidating basic molecular mechanisms that control mucosal wound repair and in developing novel therapeutic strategies aimed at promoting repair of the damaged epithelium.