Harvard Catalyst Profiles

Alcoholic hepatitis (AH) is a severe form of alcoholic liver disease (ALD) with a >30% mortality within 180 days after diagnosis. There is no effective therapy or reliable biomarkers to monitor disease progression and outcome. In this NIH supported study, we will assess the small and large RNA composition of circulating extracellular vesicles(EV) from patients with alcoholic hepatitis, heavy alcohol use and normal controls. Large data sets from RNA sequencing will be evaluated and correlated with clinical outcomes such as mortality, organ failure, infections. In addition, our translational research lab studies non-alcoholic steatohepatitis and fibrosis. We use mouse models to dissect the mechanistic roles of key signaling molecules identified in patient samples and test novel therapeutic interventions in preclinical models.

Alcoholic and non-alcoholic steatohepatitis (NASH) represent over 50% of liver diseases worldwide and activation of the inflammatory cascade contributes to disease progression. There is also emerging evidence about alcohol use accelerating NASH that is the liver manifestation of the metabolic syndrome, obesity and insulin resistance/Type 2 diabetes. This project will aim to answer critical questions related to key determinants of disease progression and clinical outcomes using bedside to bench approaches. We will utilize human biospecimens prospectively collected in the AlcHepNet clinical trial to evaluate the functional, phenotypic and metabolomic characteristics of major circulating immune cell populations in the well-defined patient populations including: severe alcoholic hepatitis (AH), heavy drinkers and healthy controls. We will particularly focus on circulating immune cells as “liquid biopsy” tools for biomarker discovery in assessing immunosuppression, parameters associated with infections and response to therapy in AH patients. Using preclinical models, we will test immunometabolic profiles in a mouse model of NASH and the combination of NASH and alcohol binge drinking. These experiments will likely reveal new mechanisms and potential therapeutic targets related to metabolic reprogramming of immune cells my metabolic insults that promote long-term inflammation and fibrosis progression.