Gastroenterology & Hepatology
Dr Stuart McPherson
An assessment of the role of endoplasmic reticulum (ER) stress in the pathogenesis of HCV-related liver injury
Hypothesis
Accumulated evidence from clinical studies indicates that patients with chronic hepatitis C virus (HCV) infection have increased risk for the development of steatosis and insulin resistance, and that obesity, steatosis and type 2 diabetes may have a role in the progression of liver injury. Recent data from experimental and animal studies show that HCV proteins and obesity may both lead to the development of ER stress. The underlying hypothesis of this study is that in patients with chronic HCV infection, ER stress contributes to steatosis, oxidative stress, NF?B activation and apoptosis, leading to liver injury and impaired insulin signalling. We also hypothesise that in patients with chronic HCV, co-existent obesity will further increase ER stress.
Significance
The underlying pathogenesis of liver injury in HCV infection is largely unknown. A greater understanding of the pathogenesis of HCV related liver injury will enable specific therapies to be developed that may prevent disease progression.
Overall aim:
To investigate the role of endoplasmic reticulum stress in the pathogenesis of HCV-induced liver injury.
Specific Aims
- To determine the relationship between expression of markers of ER stress and severity of histological features of liver injury (steatosis, inflammation, fibrosis) in patients infected with HCV genotypes 1 or 3.
- Determine the relationship between host metabolic factors (obesity, type 2 diabetes, insulin resistance) and expression of markers of ER stress in patients with chronic HCV.
- Examine the mechanisms by which ER stress may contribute to liver injury in patients with chronic HCV. This will involve assessment of the relationship between markers of ER stress and NF?B activation, expression of proinflammatory mediators and apoptosis.
Goals for grant period
To complete the laboratory work for the project and perform data analysis. Some preliminary results have been accepted for presentation at the American Liver Meeting, Boston November 2007. Following complete data analysis, a manuscript will be prepared and submitted for publication.
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