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Thesis Research Summary:
Worldwide, more than 800,000 people die from end-stage liver fibrosis, or cirrhosis, each year. It is the third leading cause of death after heart disease and cancer in the United States population aged between 45 and 65.
Liver fibrosis is the process of wound healing where the liver can respond to an insult resulting in the excessive accumulation of extracellular matrix (ECM) components, such as collagen, leading to scar tissue. Any type of liver injury can trigger an inflammatory response leading to activation of hepatic stellate cells (HSCs). Once activated, HSCs proliferate, differentiate into myofibroblasts, and are one of the major producers of ECM proteins in the injured liver. Recently, it has been demonstrated that advanced glycation end products (AGEs), a group of molecules that result from the reaction of proteins with sugars trigger the production of reactive oxygen species (ROS). Accumulation of ROS can induce the activation and proliferation of HSCs. Furthermore, increased serum levels of AGEs in individuals with hepatic fibrosis positively correlate with the severity of fibrosis. Elevated serum levels of AGEs are also seen in individuals with diabetes with liver complications. Recently, our lab has demonstrated that treatment of collagen with an AGE precursor can induce fibroblasts to differentiate to myofibroblasts and express more collagen. Thus, these data are suggestive that the involvement of AGEs may, in some cases, precipitate the formation of myofibroblasts in the liver leading to the excessive accumulation of collagen. One of the goals of my thesis project is to determine the effects of AGE-treated collagen in migration and proliferation of activated HSCs. |