Role of ClC-2 and NHE transport proteins in Intestinal Mucosal Barrier

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Title: Role of ClC-2 and NHE transport proteins in Intestinal Mucosal Barrier
Author: Nighot, Prashant Keshav
Advisors: Dr. Anthony Blikslager, Committee Chair
Dr. Sam Jones, Committee Member
Dr. Jody Gookin, Committee Member
Dr. Mathhew Koci, Committee Member
Abstract: Intestinal mucosal barrier recovery is critical to prevent entry of pathogens and toxic products in various patho-physiological conditions. We studied role of ion transporters in the recovery of intestinal barrier function after ischemic injury and found that the mice lacking ClC-2 Chloride channel or Sodium Hydrogen exchanger NHE2 have impaired barrier recovery as shown by epithelial restitution independent in vivo blood-to-lumen clearance of a labeled probe. Further ultrastructural, biochemical, and histochemical analysis clearly revealed that the impaired barrier recovery in both models is mediated through inadequate assembly of the intracellular tight junctions. As we came across evidences about increased association between ClC-2 and the tight junction protein occludin during barrier recovery, we speculate that ClC-2 might act as scaffold protein in the reassembly of tight junctions. The mechanism of NHE2 mediated tight junction recovery could involve NHE regulatory protein EBP50. These in vivo studies in genetically modified mice confirm earlier pharmacological and ex vivo studies and underscore importance of ion transport proteins in the dynamic regulation of tight junctions. In another piece of study we investigated role of ion transport in infectious diarrhea by using an experimental in vivo Turkey Astrovirus (TAstV-2) model. The study aimed at elucidating hitherto unknown mechanisms of astrovirus induced diarrhea, revealed that the astrovirus infection leads to sodium malabsorptive diarrhea and redistribution of plasma membrane sodium hydrogen exchanger NHE3, possibly associated with apical F-actin rearrangement.
Date: 2008-07-22
Degree: PhD
Discipline: Comparative Biomedical Sciences

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