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; Arriazu, Elena; Magdaleno, Fernando et al. (2018) High Mobility Group Box-1 Drives Fibrosis Progression Signaling via the Receptor for Advanced Glycation End Products in Mice. Hepatology 68:2380-2404
Magdaleno, Fernando; Blajszczak, Chuck C; Nieto, Natalia (2017) Key Events Participating in the Pathogenesis of  Alcoholic Liver Disease. Biomolecules 7:
Arriazu, Elena; Ge, Xiaodong; Leung, Tung-Ming et al. (2017) Signalling via the osteopontin and high mobility group box-1 axis drives the fibrogenic response to liver injury. Gut 66:1123-1137
Magdaleno, Fernando; Arriazu, Elena; Ruiz de Galarreta, Marina et al. (2016) Cartilage oligomeric matrix protein participates in the pathogenesis of liver fibrosis. J Hepatol 65:963-971
Laitman, Benjamin M; Asp, Linnéa; Mariani, John N et al. (2016) The Transcriptional Activator Krüppel-like Factor-6 Is Required for CNS Myelination. PLoS Biol 14:e1002467
Renault, Thibaud T; Luna-Vargas, Mark P A; Chipuk, Jerry E (2016) Mouse Liver Mitochondria Isolation, Size Fractionation, and Real-time MOMP Measurement. Bio Protoc 6:
Kocabayoglu, Peri; Zhang, David Y; Kojima, Kensuke et al. (2016) Induction and contribution of beta platelet-derived growth factor signalling by hepatic stellate cells to liver regeneration after partial hepatectomy in mice. Liver Int 36:874-82
Kocabayoglu, Peri; Lade, Abigale; Lee, Youngmin A et al. (2015) ?-PDGF receptor expressed by hepatic stellate cells regulates fibrosis in murine liver injury, but not carcinogenesis. J Hepatol 63:141-7
Renault, Thibaud T; Floros, Konstantinos V; Elkholi, Rana et al. (2015) Mitochondrial shape governs BAX-induced membrane permeabilization and apoptosis. Mol Cell 57:69-82
Hasegawa, Daisuke; Calvo, Veronica; Avivar-Valderas, Alvaro et al. (2015) Epithelial Xbp1 is required for cellular proliferation and differentiation during mammary gland development. Mol Cell Biol 35:1543-56

Showing the most recent 10 out of 90 publications