Alcoholic liver disease remains a highly prevalent and often lethal complication of alcohol abuse, whose etiology is incompletely understood. Understanding the basis of alcoholic liver disease could improve the health of millions of Americans afflicted by this problem. The overall objective of this exploratory alcohol research center is to elucidate the pathogenesis of alcoholic liver injury and fibrosis due to oxidant stress by incorporating novel models of disease and promoting unique synergistic interactions among a diverse range of investigators with complementary interests and strengths. This will advance our commitment to developing an Alcohol Research Center (P50). Specifically, we will: 1) Elucidate the mechanistic underpinnings of alcoholic liver disease by studying the roles of oxidant stress, cell-cell interactions and a novel transcriptional regulator, KLF6, in mediating liver injury and fibrogenesis;2) Define novel models of alcoholic liver injury, non-alcoholic steatohepatitis (NASH) and fibrosis through the use of zebrafish, engineered mammalian cell lines, and transgenic models of alcohol-induced liver injury in mice;3) Forge new, synergistic interactions among investigators at the Mount Sinai School of Medicine to create novel approaches to understanding alcoholic liver injury and fibrosis;4) Create new educational and training opportunities to study alcoholic liver injury and fibrosis by leveraging existing NIH-funded training programs, and by establishing annual symposia and regular seminars in topics related to alcoholic liver disease. To address these aims, the Center will include an Administrative and two Research Cores (a Models Core that will include both mammalian and zebrafish reagents and animal models;and a Morphology Core led by a highly experienced hepatopathologist);Two Exploratory Projects: a) Hepatic injury, fibrosis and alternative splicing of the KLF6 gene in response to oxidant stress;b) zebrafish as a model for alcoholic liver disease;Three Pilot Feasibility Projects;a) Effects of alcohol-mediated liver injury on growth hormone biology;b) Cdc37 an early biomarker of alcohol induced hepatocellular carcinoma and the role HspQO inhibitors as therapeutic agents;c) Effect of alcohol on mouse and human embryonic stem cell-derived hepatoblasts. Collectively, the highly collaborative nature of the program promises to yield important new insights into the molecular basis of alcoholic liver injury using novel models and state-of-the-art methods.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Exploratory Grants (P20)
Project #
5P20AA017067-05
Application #
8308020
Study Section
Special Emphasis Panel (ZAA1-BB (90))
Program Officer
Radaeva, Svetlana
Project Start
2008-08-01
Project End
2013-07-31
Budget Start
2012-08-01
Budget End
2013-07-31
Support Year
5
Fiscal Year
2012
Total Cost
$441,045
Indirect Cost
$180,841
Name
Icahn School of Medicine at Mount Sinai
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
078861598
City
New York
State
NY
Country
United States
Zip Code
10029
Ge, Xiaodong; Antoine, Daniel J; Lu, Yongke et al. (2014) High mobility group box-1 (HMGB1) participates in the pathogenesis of alcoholic liver disease (ALD). J Biol Chem 289:22672-91
Renault, Thibaud T; Elkholi, Rana; Bharti, Archana et al. (2014) B cell lymphoma-2 (BCL-2) homology domain 3 (BH3) mimetics demonstrate differential activities dependent upon the functional repertoire of pro- and anti-apoptotic BCL-2 family proteins. J Biol Chem 289:26481-91
Howarth, Deanna L; Lindtner, Claudia; Vacaru, Ana M et al. (2014) Activating transcription factor 6 is necessary and sufficient for alcoholic fatty liver disease in zebrafish. PLoS Genet 10:e1004335
Jiao, Jingjing; Dragomir, Ana-Cristina; Kocabayoglu, Peri et al. (2014) Central role of conventional dendritic cells in regulation of bone marrow release and survival of neutrophils. J Immunol 192:3374-82
Arriazu, Elena; Ruiz de Galarreta, Marina; Cubero, Francisco Javier et al. (2014) Extracellular matrix and liver disease. Antioxid Redox Signal 21:1078-97
Ge, Xiaodong; Leung, Tung-Ming; Arriazu, Elena et al. (2014) Osteopontin binding to lipopolysaccharide lowers tumor necrosis factor-* and prevents early alcohol-induced liver injury in mice. Hepatology 59:1600-16
Lu, Yongke; Ward, Stephen C; Nieto, Natalia (2014) Ethanol plus the Jo2 Fas agonistic antibody-induced liver injury is attenuated in mice with partial ablation of argininosuccinate synthase. Alcohol Clin Exp Res 38:649-56
Vacaru, Ana M; Unlu, Gokhan; Spitzner, Marie et al. (2014) In vivo cell biology in zebrafish - providing insights into vertebrate development and disease. J Cell Sci 127:485-95
Wang, Xiaodong; Lopategi, Aritz; Ge, Xiaodong et al. (2014) Osteopontin induces ductular reaction contributing to liver fibrosis. Gut 63:1805-18
Vacaru, Ana M; Di Narzo, Antonio Fabio; Howarth, Deanna L et al. (2014) Molecularly defined unfolded protein response subclasses have distinct correlations with fatty liver disease in zebrafish. Dis Model Mech 7:823-35

Showing the most recent 10 out of 62 publications