Biophysical analysis of proteins that contribute to liver damage and liver regeneration
Florence, Quentin Jerod Tekel
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The liver is a vital organ and is unique in that it is capable of regeneration. The work presented herein is focused on the biophysical and structural characterization of the hepatitis B virus surface protein HBsAg (the current hepatitis b vaccine) and the protein Augmenter of Liver Regeneration (a growth factor isolated from weanling or regenerating liver). Hepatitis b is a blood-born-associated virus that has infected over 2 billion people worldwide and can lead to liver cancer. Thus, one of the overall goals of this study is to provide biophysical and structural information for the hepatitis b vaccine antigen HBsAg. The lack of an HBsAg structure has prevented us from understanding the effects of mutations of the viral polymerase, which can lead to vaccine escape and has impeded the development of bivalent vaccines. The goal of this work is to provide biochemical and structural information about HBsAg that can be used in the design of new and better vaccines. Liver damage and regeneration have been the focus of research studies for decades. From these studies a growth factor called Augmenter of Liver Regeneration (ALR) was identified that augmented the regeneration process. ALR was then shown to be homologous the yeast Saccharomyces cerevisiae protein Erv1 (Essential for Growth and Respiration protein 1) which has been demonstrated to be involved in the mitochondrial intermembrane space import (IMS) pathway. The IMS pathway has been well characterized in yeast and shows that Erv1 interacts with mitochondrial intermembrane assembly protein 40 (Mia40) and cytochrome c forming a Mia40 – ERV1 – cytochrome c redox chain. The goal of these studies is focused on characterizing the mammalian equivalent of the Mia40 – ALR – cytochrome c redox chain using Rattus norvegicus as a model. These studies will include the recombinant cloning, expression, purification of rat Mia40 and ALR and the charaterization of interactions between the Mia40, ERV1 and cytochrome c proteins in solution. Together these studies should provide a foundation for the development of new tools that can be used to prevent liver damage and/or promote liver repair.
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