Shiga toxin-producing E. coil (STEC) is an emerging infectious pathogen that causes in excess of 30,000 cases of disease per year in the United States. STEC, including E. coil O157:H7, is also the leading cause of acute renal failure, hemolytic uremic syndrome (HUS), in young children. No effective preventive modality or therapeutic intervention is currently available for this disease. This project is designed to more fully describe a """"""""window of opportunity"""""""" available for treatment and prevention of STEC-associated acute renal failure. In most cases, a three to nine day period of renal inflammation takes place between the appearance of bloody diarrhea and the onset of acute renal failure. It is believed that STEC virulence factors such as Shiga toxin (Stx2) and lipopolysaccharide (LPS) are the primary initiators of the renal disease. These factors elicit production of pro-inflammatory host cytokines and chemokines. This study utilizes a murine model to define the cytokines and chemokines involved and describe how these agents cause migration and accumulation of inflammatory cell types in the kidney. These cell types include neutrophils, monocytes/macrophages and platelets. Mice with mutated cytokine, chemokine, or adherence factor genes are to be employed to determine which of these factors are required in the disease process. In addition, adherence of these cell types to isolated endothelial cells under flow conditions is included to define the inflammatory action of Stx2 and LPS. Studies are also included to show how host cytokines and chemokines further sensitize endothelial cells to Stx2 by activation of intracellular signal transduction pathways. The goal of these studies is to reveal the opportunities available for effective application of therapeutic agents in STEC-associated renal disease.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI024431-20
Application #
6846239
Study Section
Special Emphasis Panel (ZRG1-BM-1 (05))
Program Officer
Schmitt, Clare K
Project Start
1990-04-01
Project End
2007-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
20
Fiscal Year
2005
Total Cost
$379,431
Indirect Cost
Name
University of Virginia
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
065391526
City
Charlottesville
State
VA
Country
United States
Zip Code
22904
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