>> *Dissertation Defense Reminder >> 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 <http://www.gmu.edu/resources/visitors/findex.html> >> >> *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. >> >> ### >