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Project Title:
HMGB1 Alteration Tight Junction Structure and Function
Funding Agency:
National Institutes of Health
Total Project Period:
Sep 1, 2004 – Aug 31, 2009
Principal Investigator:
Penny L. Sappington, M.D
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Co-Investigator(s):
Mitchell P. Fink, MD; Russell Delude, PhD; Xiaonan Han, PhD; Joan Lakoski, PhD
Project Summary:
The intestinal epithelium normally functions as a selective barrier, permitting the absorption of nutrients, electrolytes, and water, but restricting the passage from the lumen into the systemic compartment of larger, potentially toxic compounds or microbes. High Mobility Group B protein 1 (HMGB1), a non-histone nuclear protein with high electrophoretic mobility,1 recently has been identified as a late-acting pro-inflammatory cytokine in patients with septic and hemorrhagic shock. We recently showed that HMGB1 also increases the permeability of cultured Caco-2 human enterocytic monolayers and causes gut barrier dysfunction in mice. The long-term goal of the studies proposed herein is to advance our understanding of the mechanisms underlying HMGB1-mediated organ dysfunction in critical illness. The governing hypothesis of this proposal is that HMGB1 causes cytopathic effects in intestinal epithelial cells by modulating the expression, targeting and/or function of the proteins that comprise the tight junctions between adjacent cells. In order to systematically address this hypothesis, we have organized our proposed work under four interrelated Specific Aims.
A.1 Specific Aim I: Determine whether HMGB1 alters the expression of tight junction proteins in gut epithelium in Caco-2 human intestinal epithelial cells through a nitric oxide (NO·)-dependent mechanism.
A.2 Specific Aim II: Determine whether HMGB1 alters the expression of tight junction proteins in gut epithelium, liver, lung, and kidney in mice.
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