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Project Title:
Molecular Biology of Hemorrhagic Shock: Project II, Molecular Basis for Epithelial Barrier Dysfunction
Funding Agency:
National Institutes of Health
Total Project Period:
Jul 01, 2004 - Jun 30, 2009
Principal Investigator:
Mitchell Fink, MD
Co-Investigator(s):
Russell Delude, PhD
Project Summary:
This project has four Specific Aims. Aim 1 is to test the hypothesis that hemorrhagic shock (HS) in mice leads to alterations in tight junction (TJ) structure and function in multiple epithelia via mechanisms that depend on the formation of nitric oxide (NO·), reactive oxygen species (ROS), and/or peroxynitrite (ONOO-). Aim 2 is to test the hypothesis that hemorrhagic shock and resuscitation (HS/R)-induced derangements in gut, liver and lung epithelial TJ structure and function are mediated, at least, in part by binding of HMGB1 and/or other related ligands to the receptor for advanced glycation end-products (RAGE). Aim 3 is to test the hypothesis that IL-6 is a key mediator of HS/R-induced derangements in gut, liver and pulmonary epithelial TJ structure and function. Aim 4 is to test the hypothesis that timely treatment with nictoninamide adenine dinucleotide (NAD+) can ameliorate HS/R-induced alterations in gut, lung, and liver epithelial dysfunction.
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