This application, a translational component of a U01 Consortium of UMMS, Cleveland Clinic, UTSouthwestern and U Louisville, explores novel therapies and biomarker discoveries in AH. Direct effects of alcohol on hepatocytes, increased intestinal permeability and activation of the innate immune system (Kupffer cells) by gut-derived LPS are major factors in AH leading to over-activation of the pro-inflammatory cascade. Currently, there are no effective strategies in AH. Our data in a mouse model demonstrated that deficiency of IL-1R or inhibition of IL-1R signaling by administration of an IL-receptor antagonist significantly attenuated steatosis and inflammatory cytokine induction in alcoholic liver disease. We also identified that microRNA-155 is an alcohol-induced regulator of increased Kupffer cell activation and TNF production in ALD. Furthermore, increased circulating levels of microRNAs correlated with liver injury and inflammation identifying them as potential biomarkers.
The aims of this U01 application are to 1) evaluate novel therapeutic targets to attenuate inflammation in AH using bench-to-bedside approaches, and to 2) identify unique biomarkers for diagnostic and therapeutic decisions in AH. The following Aims will be investigated:
Aim #1 : To identify and validate novel biomarkers of AH associated with mild-moderate and severe disease and response to therapy by exploring a) circulating microRNAs as markers of mild-moderate and severe AH and/or response to therapy, b) TLR4 tolerance in monocytes as a biomarker of disease severity and/or response to therapy and c) circulating unique biomarkers of systemic inflammation, gut permeability, liver injury and regeneration.
Aim #2 : To test IL-1 inhibition as a novel therapeutic strategy in alcoholic hepatitis using translational approaches.
Aim #3 : To identify unique new drug targets for treatment of AH using a translational approach to test Farnesoid X Receptor agonists and miRNA-155 inhibition in preclinical studies.

Public Health Relevance

Translational Alcoholic liver disease (ALD) is one of the most common liver diseases in the world. Alcoholic hepatitis (AH) has high mortality and morbidity with limited treatment options. This application explores novel therapies and biomarker discoveries in AH to translate preclinical data from bench research to bedside applications. The aims of this translational UO1 application are to 1) evaluate novel therapeutic targets to attenuate inflammation in AH using bench-to-bedside approaches, and to 2) identify unique biomarkers for diagnostic and therapeutic decisions in alcoholic hepatitis.

Agency
National Institute of Health (NIH)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA021907-03
Application #
8692621
Study Section
Special Emphasis Panel (ZAA1)
Program Officer
Wang, Joe
Project Start
Project End
Budget Start
Budget End
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
Worcester
State
MA
Country
United States
Zip Code
01655
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Bukong, Terence N; Iracheta-Vellve, Arvin; Gyongyosi, Benedek et al. (2016) Therapeutic Benefits of Spleen Tyrosine Kinase Inhibitor Administration on Binge Drinking-Induced Alcoholic Liver Injury, Steatosis, and Inflammation in Mice. Alcohol Clin Exp Res 40:1524-30
Bukong, Terence N; Iracheta-Vellve, Arvin; Saha, Banishree et al. (2016) Inhibition of spleen tyrosine kinase activation ameliorates inflammation, cell death, and steatosis in alcoholic liver disease. Hepatology 64:1057-71
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Momen-Heravi, Fatemeh; Saha, Banishree; Kodys, Karen et al. (2015) Increased number of circulating exosomes and their microRNA cargos are potential novel biomarkers in alcoholic hepatitis. J Transl Med 13:261
Szabo, Gyongyi; Satishchandran, Abhishek (2015) MicroRNAs in alcoholic liver disease. Semin Liver Dis 35:36-42
Momen-Heravi, Fatemeh; Bala, Shashi; Bukong, Terence et al. (2014) Exosome-mediated delivery of functionally active miRNA-155 inhibitor to macrophages. Nanomedicine 10:1517-27