Excessive alcohol consumption is a major global public health issue, with alcoholic liver disease (ALD) being a leading cause of liver-related death in the United States. Alcoholic hepatitis (AH), at up to a 20% lifetime occurrence rate, is a particularly serious form of ALD with high short term mortality rates. This work focuses on the application of sensitive liquid chromatography-mass spectrometry (LC-MS) platforms for the broad detection and quantification of protein abundances towards the molecular mechanistic study of AH. Significant previous work has been performed in the application of proteomic technologies towards the study of liver related diseases, but it has not been applied clinically to investigate AH. Such technologies have the ability to provide an unbiased view of key biofluids, cells, and tissues, where there is limited understanding concerning the mechanistic onset of AH, the molecular signatures of disease progression, and importantly any signatures which can help determine treatment outcomes and assess new treatment regiments. We will apply both discovery and verification-based proteomic technologies towards the investigation of AH in conjunction with a clinical trial using blood plasma, liver tissue, and isolated circulating blood cells, to determine the differentiating set of expressed and/or secreted proteins for patients undergoing corticosteroid and anti-cytokine treatment. The goals of this study will be to identify and verify key molecular markers and integrated pathways which would clarify understanding of the mechanism of AH disease progression and potential treatment effects. Correlation, integration, and functional mapping of the protein-level results with complementary studies performed across the U01 consortium will provide important context to initial findings and interpretations at the systems level.
Alcoholic liver disease (ALD) is a leading cause of liver-related death in the United States with alcoholic hepatitis (AH) being a particularly serious form of ALD with high short term mortality rates. Application of proteomic technologies will act in a synergistic manner across the U01 consortium in the study of AH for the identification and quantification of proteins and pathways mechanistically linked to AH onset, progression, treatment, and outcome.