Redox Signaling and AMPK Crosstalk on Alcohol-Induced Multi-Organ Damage: Liver and Adipose TIssue - The goal of the application is to define the interaction among superoxide dismutase 1 (SOD1), adenosine monophosphate-activated protein kinase (AMPK), and catalase in modulating liver injury induced by ethanol exposure. Additionally, there is a strong link between alcohol-associated liver disease (ALD) and adipose tissue dysfunction. Although SOD1 is known to inhibit the progression of ALD, very little is known regarding mechanisms involved in mediating the hepatoprotective effects of SOD1. Thus, there is an urgent need to define mechanisms by which SOD1 modulates ALD and to develop novel therapies to ameliorate this alcohol-related morbidity. Central to our hypothesis is that SOD1-mediated redox regulation of AMPK and catalase inhibits exosome biogenesis and/or promotes ethanol clearance, thereby attenuating ALD, and that a novel mannose receptor-targeted SOD1 nanoparticles (Man-Nano), is an effective agent in attenuating ALD. The studies will employ genetic, molecular, and pharmacological approaches to examine the interplay among SOD1, AMPK signaling, and catalase in modulating ALD and to demonstrate the effectiveness of Man-Nano in ameliorating ALD. We hypothesize that SOD1 increases intracellular H2O2 thereby increasing AMPK/catalase activities in hepatocytes and/or adipocytes, which contribute to the protective effects of SOD1 against ALD. We will test this hypothesis by manipulating levels of SOD1 in hepatocytes and adipocytes as presented in the following three aims. In the first aim, we will use hepatocyte-specific SOD1 knock-out mice to determine the role and mechanisms of hepatocyte SOD1 in modulating ethanol-induced liver injury. Studies in Aim 2 will employ adipocyte-specific SOD1 knock-out mice to determine the role and mechanisms of adipocyte SOD1 in modulating ethanol-induced adipose tissue and liver injury. In our last aim, we will determine the efficacy and mechanism of action of Man-Nano in ameliorating ethanol-induced liver and adipose tissue injury. Overall, this project will provide critical information regarding the novel mechanism(s) by which SOD1 attenuates ALD. Completion of this project will also yield insight into the therapeutic impact of a novel antioxidant-based therapy (i.e. Man-Nano) in ameliorating ethanol-induced organ injury.
