Targeting oxidized phospholipids by AAV-mediated gene therapy in nonalcoholic fatty liver disease

Upchurch, Clint, Pharmacology - School of Medicine, University of Virginia
Leitinger, Norbert, Pharmacology, University of Virginia

Oxidized phospholipids are a diverse class of molecules that have been implicated in nearly all pathologies involving oxidative stress. Here, we will examine the role of oxidized phospholipids in a murine model of non-alcoholic fatty liver disease as well as investigate the complexity of the oxophospholidome in critically ill patients. In the first part of this dissertation, we developed an AAV8-mediated gene therapy to express a neutralizing antibody fragment against oxidized phospholipids. We inoculated mice either prophylactically or after the development of hepatic steatosis and were able to neutralize plasma oxidized phosphatidylcholine (OxPC) species, lowering their concentrations, as well as protect mice from developing hepatic steatosis or hepatic fibrosis. In the second part of this dissertation, we identified and quantified OxPC species present in plasma of critically ill patients. We determined concentration ranges of individual OxPC species and discovered that classes of OxPC species associated with unique clinical parameters suggesting specific roles of OxPC species in different pathologies. In conclusion, we have developed a suite of tools to interrogate the role of OxPCs in vivo directly which will provide novel insight into the function of OxPCs in diverse pathologies.  

PHD (Doctor of Philosophy)
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