20.109(S10):Notebook/Orange w/f

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Project Summary

  • In patients with celiac disease, ingested gluten is broken down into gliadin like normal, but then triggers an autoimmune response through both the innate and adaptive immune systems. Enterocytes that absorb gliadin express the stress marker major-histocompatibility-complex class I chain relatedA (MIC-A), activing a cytotoxic response by natural-killer cells. Gliadin also binds to the CXCR3 receptor on the enterocyte membrane, inducing expression of Zonulin, a protein that disrupts the tight junctions in the intestinal lining. Once the membrane is sufficiently disrupted, gliadin passes through the membrane, where it is recognized by the adaptive immune system. The resulting inflammatory cascade leads to a release of cytokines that induce production of metalloproteins and tissue damaging proteins resulting in intestinal villi atrophy and crypt hyperplasia. We plan on developing a method to block the CXCR3 receptor to limit the damaging effects of gluten consumption.

Literature Review

K. Lammer et al. Gliadin Induces an Increase in Intestinal Permeability and Zonulin. Release by Binding to the Chemokine Receptor CXCR3Gastroenterology. 2008 July ; 135: 194–204

  • Gliadin Induces an Increase in Intestinal Permeability and Zonulin
  • Release by Binding to the Chemokine Receptor CXCR3: Upon gliadin binding to the CXCR3 receptor on the enterocyte membrane in celiac patents, Zonulin is expressed and released in a MyD88 dependent response. Zonulin then acts like the zonula occludens toxin produced by cholera to disrupt the tight junctions between epithelial cells in the intestine, allowing gliadin to pass through the lining and trigger an autoimmune response against intestinal villi.

Schuppan D, Junker Y, Barisani D. Celiac disease: from pathogenesis to novel therapies. Gastroenterology 2009; 137:1912-33

  • Therapies for celiac disease are needed to reduce high cost of maintaining a gluten free diet and to reduce symptoms caused by contaminated “gluten free” foods. There are several potential therapies for celiac disease. Oral enzyme therapy can be used to digest abundant proline residues in gliadin. These enzymes are naturally found in several microorganisms. The gluten can also be shielded in the small intestine using gluten antibodies found in cows. Moreover, zolulin, a protein that increase epithelium permeability to gluten, can be inhibited to ultimately decrease the gluten induced inflammatory response.
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