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[log in to unmask]" type="cite">Dissertation Defense Announcement
To:  The George Mason University Community


Candidate: Sandra J. Page
Program:    PhD Biosciences

Date:   Monday August 29, 2011
Time:   2:00 p.m. 
Place:  George Mason University
 	     Discovery Hall Auditorium
	     Prince William campus
  
Dissertation Chair: Dr. Ancha Baranova
Committee members: Dr. Emanuel Petricoin III, Dr. James D. Willett, Dr. Gregory Foster

Title: "Novel Biomarkers for Non-Alcoholic Fatty Liver Disease
	  and Associated Symptoms"

The dissertation is on reserve in the Johnson Center Library, Fairfax campus.
The doctoral project will not be read at the meeting, but should be read in advance. 

All members of the George Mason University community are invited to attend.


ABSTRACT: 
  

Obesity is on the rise in populations across the world, and represents a major health concern. It is a component of Metabolic Syndrome, a collection of risk factors that predispose to diabetes and cardiovascular disease. Metabolic Syndrome is often accompanied by non-alcoholic fatty liver disease (NAFLD), a spectrum of liver disease ranging from simple steatosis, to non-alcoholic steatohepatitis (NASH) and liver fibrosis. Currently, the gold standard for NASH and liver fibrosis diagnostics is liver biopsy; thus, a non-invasive procedure for detecting and staging NAFLD is greatly needed. The dissertation work to be presented involved evaluating various kinds of serum-based, soluble molecules as biomarkers of NASH, NASH-related fibrosis, or its associated symptoms. In the first study, a biomarker panel for NASH and NASH-related fibrosis was developed by screening several proteins previously associated with liver disease but never tested in combination; these included hormones derived from adipose tissue (adipokines) and proteins involved in fibrogenesis and cell death. The resulting panel outperformed previously reported biomarkers of NASH and hepatic fibrosis, and it is anticipated that subsequent testing of this panel on larger populations of NAFLD patients will ultimately support its use in clinical settings.

            A second study was conducted with the goal of discovering novel, as-of-yet untested biomarkers of NASH and NASH-related fibrosis that may be tied to the deregulation of cell signaling pathways in adipose tissue. A previous study using a phosphoproteomic approach showed that several kinase-driven pathways were deregulated in the adipose tissue of patients with NASH and NASH-related fibrosis. Enrichment analysis on this data set showed that these pathways were linked to the regulation of cell functions by insulin. A subsequent pathway analysis was then conducted to identify a set of secreted, soluble proteins associated with these pathways. From this analysis two promising candidates were selected based on extensive literature searches; these were the chemokine CCL-2/MCP-1, and soluble Fas ligand. These candidates were then tested on a small cohort of patients with NASH and NASH-related fibrosis to determine if they had the potential to be diagnostically predictive, and it was discovered that both worked reasonably well as biomarkers of fibrosis. Consequently, these molecules may be released at abnormal levels by adipose tissue in patients with NAFLD and may in turn play a role in fibrogenesis associated with NASH; they would therefore be good candidates to test in future development of biomarker panels for NASH-related fibrosis.

            A third study was undertaken to evaluate the association between levels of various soluble molecules and fatigue in patients with NAFLD or hepatitis C. Specifically, we correlated self-reported assessments of fatigue dissecting this condition into fatigue associated with physical activity (peripheral fatigue) or more global lack of energy and motivation (central fatigue) with measures of inflammation, or with abnormalities of glucose and lipid metabolism. The study demonstrated that a substantial majority of patients with chronic liver disease report significant peripheral fatigue. This type of fatigue was linked to elevated serum levels of IL-6 and IL-8, linking it to an inflammatory component, which is not the case for central fatigue.

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