Alcohol and tissue injury, from mechanisms to treatments

ABSTRACT Alcohol abuse is a leading cause of morbidity and mortality worldwide and recent data indicate that alcoholic liver disease affects over 10 million Americans. In addition to the classically appreciated impact of alcohol use on the liver, injury to other organs, such as the intestine, skeletal muscle, kidney, adipose tissue and the neural system contribute to morbidity and mortality associated with chronic alcohol abuse. Understanding both the common and tissue-specific mechanisms by which ethanol impairs cellular and organ function will lead to the development of rationally designed therapeutic interventions to both prevent and reverse tissue damage and disease resulting from chronic alcohol consumption. The overall goal of the Northern Ohio Alcohol Center (NOAC) is to identify specific molecular targets of ethanol-induced damage, as well as understand the complex adaptive and maladaptive responses of cells and systems to damage. This information will enable us to 1) target therapeutic interventions that will either slow and/or reverse the progression of alcohol-induced organ injury and 2) develop biomarkers that reflect injury and will be useful in the future for testing of the efficacy of novel therapeutic strategies in relevant clinical populations. NOAC brings together an outstanding team of interdisciplinary investigators and is supported by an Administrative Core, an Animal Models and Cell Isolation Core, a Clinical Core and a Pilot Projects Core. NOAC utilizes outstanding state-of-the-art facilities at 3 premier research institutions in Cleveland, Cleveland Clinic, Case Western Reserve University and MetroHealth Hospital, as well as at our ancillary sites at Northeast Ohio Medical University, University of Toledo and Nationwide Children’s Hospital at the Ohio State University. Four Research Components (RC) are proposed: RC1 (Brown) investigates the interaction between ethanol, gut microbial metabolites and circadian clocks and tests “drug-the-bug” strategies to prevent injury, RC2 (Davalos) interrogates the impact of ethanol activation of microglial cells and neuroinflammation using state-of-the-art live imaging two photon microscopy; RC3 (Dasarathy) is designed to understand the impact of chronic ethanol on skeletal muscle wasting, a critical co-morbid feature of alcoholic liver disease and tests the efficacy of targeted nutrients to prevent sarcopenia and RC4 (Nagy) investigates cell specific mechanisms of hepatocellular death via necroptosis/apoptosis and develops circulating biomarkers for liver injury. The long-term goal of NOAC is to translate novel findings on the specific mechanisms by which ethanol disrupts cellular and organ function into effective treatment strategies for patients with alcoholic tissue injury. Our outstanding investigative team and excellent Core facilities will continue to work collaboratively to address key mechanistic and translational problems of alcohol-induced tissue injury, providing unique strengths for translating novel findings the molecular and cellular mechanisms of ethanol action and disease progression into the development of treatment strategies.