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Discovering the Molecular Mechanisms that Regulate Tissue Barriers

Research Summary: Inflammatory Bowel Diseases (IBDs), encompassing both Crohn’s Disease and Ulcerative Colitis, is a multifactorial disease involving recurring immune activation and progressive degradation of the gut lining. Standard therapies ameliorate inflammatory symptoms without addressing the underlying causes of disease. Indeed, IBD pathogenesis is believed to involve complex interactions between genetic abnormalities and environmental factors such as a high fat, low fiber western diet. Additionally, IBDs confer significant long-term morbidities as well as an increased risk of carcinogenesis. Therefore, it is vital that we investigate new therapeutic strategies in light of these complexities.

The gut lining (or mucosa) forms a regulatable physical barrier to ions, antigens, and pathogens. Failure of this barrier leads to inflammation. The effectiveness of this lining is due in part to paracellular protein structures called tight junctions. The tight junction paracellular seal relies on claudins, a large protein family, a few of which are capable of forming ion pores between cells. Studies have shown that the loss of the mucosal barrier is a unifying etiological feature of human IBD; and includes changes in claudin protein expression. Furthermore, proinflammatory cytokines such as Tumor necrosis factor-alpha and Interferon-gamma alter claudin protein expression and decrease overall mucosal integrity. Therefore, the focus of my lab is to better understand how the intestinal lining maintains an effective barrier, how this is compromised during disease.

My lab studies claudin function and regulation under both physiological and inflammatory conditions. We use a number of complementary approaches to explore the molecular aspects of claudin regulation, combining in vitro cell culture studies with mouse models of colitis. Furthermore, we are taking advantage of the well-studied model organism, C. elegans, a small roundworm that will allow us to discover the genetic pathways regulating claudin function. Our aim is to discover the molecular underpinnings of IBD with the hope that this will lead us to better, more effective treatments.

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