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)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
3U01AA021907-03S1
Application #
8933075
Study Section
Special Emphasis Panel (ZAA1-JJ (07))
Program Officer
Wang, Joe
Project Start
2012-09-15
Project End
2017-06-30
Budget Start
2014-09-27
Budget End
2015-06-30
Support Year
3
Fiscal Year
2014
Total Cost
$48,575
Indirect Cost
$19,575
Name
University of Massachusetts Medical School Worcester
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
603847393
City
Worcester
State
MA
Country
United States
Zip Code
01655
Saha, Banishree; Momen-Heravi, Fatemeh; Furi, Istvan et al. (2018) Extracellular vesicles from mice with alcoholic liver disease carry a distinct protein cargo and induce macrophage activation through heat shock protein 90. Hepatology 67:1986-2000
Ambade, Aditya; Lowe, Patrick; Kodys, Karen et al. (2018) Pharmacological inhibition of CCR2/5 signaling prevents and reverses alcohol-induced liver damage, steatosis and inflammation in mice. Hepatology :
Lowe, Patrick P; Gyongyosi, Benedek; Satishchandran, Abhishek et al. (2017) Alcohol-related changes in the intestinal microbiome influence neutrophil infiltration, inflammation and steatosis in early alcoholic hepatitis in mice. PLoS One 12:e0174544
Iracheta-Vellve, Arvin; Petrasek, Jan; Gyogyosi, Benedek et al. (2017) Interleukin-1 inhibition facilitates recovery from liver injury and promotes regeneration of hepatocytes in alcoholic hepatitis in mice. Liver Int 37:968-973
Szabo, Gyongyi; Momen-Heravi, Fatemeh (2017) Extracellular vesicles in liver disease and potential as biomarkers and therapeutic targets. Nat Rev Gastroenterol Hepatol 14:455-466
Cheng, Ming; An, Shoukuan; Li, Junquan (2017) Identifying key genes associated with acute myocardial infarction. Medicine (Baltimore) 96:e7741
Saha, Banishree; Momen-Heravi, Fatemeh; Kodys, Karen et al. (2016) MicroRNA Cargo of Extracellular Vesicles from Alcohol-exposed Monocytes Signals Naive Monocytes to Differentiate into M2 Macrophages. J Biol Chem 291:149-59
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
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
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

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