? Delayed graft function (DGF) independently predicts reduced 1- and 5- year kidney transplant survival and contributes to the development of chronic allograft nephropathy (CAN). DGF is caused by both cold and warm ischemia. Cold ischemia occurs during both pulsatile machine perfusion and static cold storage of kidneys. This grant will focus on the pathophysiology of cold and warm ischemia and specifically the role of caspases. Caspase-3 is a major mediator of apoptotic and necrotic cell death. Caspase-1 converts the proinflammatory cytokines IL-1beta and IL-18 to their active forms. The overall hypothesis is that caspases mediate proximal tubular damage in both cold and warm ischemia. In a model of cold ischemia the contribution of caspase-3 to proximal tubular apoptosis as well as severe brush border injury will be assessed. Gene expression, protein and activity of caspases-3, 7, 9 (mitochondrial pathway of apoptosis) and 8 (death receptor pathway of apoptosis) will be determined during both static and pulsatile cold ischemia. Immunohistochemistry for activated caspase-3 in proximal tubules will be performed. The effect of caspase inhibition on kidney morphology will be assessed. The findings of these experiments will contribute to the understanding of cold ischemia injury and organ preservation. Caspase-1-mediated production of IL-18 mediates ischemic ARF. IL-18 is a potent inducer of interferon gamma, which is a powerful inducer of MHC expression. Caspase-1 and IL-18-mediated increase in interferon gamma expression in the kidney and MHC expression on proximal tubules will be determined in a model of warm ischemia. Interferon gamma and MHC class I and II mRNA expression in the kidney will be assessed. The effect of caspase-1, IL-18 and interferon gamma inhibition on MHC expression will be evaluated. Reduced MHC expression is associated with decreased kidney graft immunogenicity and has important implications for the deleterious effect of DGF on both short and long-term allograft function ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Type
Clinical Investigator Award (CIA) (K08)
Project #
1K08DK069512-01A1
Application #
7036973
Study Section
Diabetes, Endocrinology and Metabolic Diseases B Subcommittee (DDK)
Program Officer
Rankin, Tracy L
Project Start
2006-09-15
Project End
2011-08-31
Budget Start
2006-09-15
Budget End
2007-08-31
Support Year
1
Fiscal Year
2006
Total Cost
$131,100
Indirect Cost
Name
University of Colorado Denver
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
041096314
City
Aurora
State
CO
Country
United States
Zip Code
80045
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