: Hepatic injury is a primary cause of liver dysfunction in both pediatric and adult patients. Our preliminary studies using an established model of murine hepatic I/R indicate that mature mice (12-13 months of age) have significantly greater liver injury after I/R than do young mice (6-8 weeks of age). These findings are consistent with clinical studies of trauma patients which suggest that pediatric patients have a far lower incidence of multiple organ dysfunction syndrome than do adult patients. The long-term goal of this proposal is to determine the molecular and cellular mechanisms that differentiate young and mature mice in their response to hepatic I/R.
Aim 1 will test the hypothesis that the transcription factor, NF-KB, is selectively depressed in hepatocytes of mature mice, leading to increased cell death and organ injury. We show that NF-KappaB activation is decreased in whole livers from mature mice, but that proinflammatory cytokine production is unaltered, suggesting that Kupffer cell activation of NF-KappaB is unaltered with age.
Aim 2 will test the hypothesis that reduced hepatic expression of HSP70 in mature mice leads to increased oxidative tissue injury and hepatocyte cell death contributing to augmented I/R injury. We provide evidence that HSP70 protein expression is reduced in livers from mature mice and that this is associated with increased hepatocellular injury of both necrotic and apoptotic mechanisms.
Aim 3 will test the hypothesis that CD4 lymphocytes serve to regulate hepatic I/R injury and that in mature mice altered function of CD4 lymphocytes contributes to augmented liver injury. Our preliminary data demonstrates that CD4-knockout mice have increased liver injury after I/R in a pattern that is identical to that observed in mature mice. We also show significant differences in the phenotypes of liver-resident lymphocytes between young and mature mice.
Aim 4 will test the hypothesis that there are a number of cell-specific alterations in the proteomes of liver cells between young and mature mice and that these changes contribute to the divergent responses to I/R injury in these age populations. We will employ proteomics to determine the subcellular proteomes of Kupffer cells, hepatocytes, sinusoidal endothelial cells, and liver-resident lymphocytes before and after I/R to identify age-related alterations. These studies will advance our understanding of the age-dependent mechanisms that differentiate the hepatic inflammatory response of adult and pediatric patient populations to acute liver injury.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Research Project (R01)
Project #
5R01AG025881-03
Application #
7233572
Study Section
Hepatobiliary Pathophysiology Study Section (HBPP)
Program Officer
Kohanski, Ronald A
Project Start
2005-06-01
Project End
2010-05-31
Budget Start
2007-06-01
Budget End
2008-05-31
Support Year
3
Fiscal Year
2007
Total Cost
$291,091
Indirect Cost
Name
University of Cincinnati
Department
Surgery
Type
Schools of Medicine
DUNS #
041064767
City
Cincinnati
State
OH
Country
United States
Zip Code
45221
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