There is a fundamental lack of understanding about the changes in molecular pathology in alcoholic hepatitis at the liver biopsy tissue level. This isa result of technical difficulties which impede the examination of liver biopsy tissue beyond the morphologic changes observed. Recently techniques have been developed in the PI's laboratory, which now make it possible to examine the changes in gene expression in liver biopsies from patients with alcoholic hepatitis. The long term goal is to better understand the changes in gene expression at the molecular level and to correlate them with the cellular morphology level. The objective in this particular application is to determine, 1) the mechanism of cell cycle arrest in alcoholic hepatitis;2) the pathophysiology of macrophages in the sinusoids in alcoholic hepatitis including their role in obstructing sinusoidal blood flow causing hypoxic injury to the hepatocytes;3) the mechanism of balloon cell degeneration of hepatocytes in alcoholic hepatitis. These questions can now be answered directly on liver biopsy tissue due to the development of new technologies such as laser capture dissection and fluorescent intensity morphometric measurements of proteins located in the different cell population. The central hypothesis is that cell cycle arrest, epigenetic transformation of balloon hepatocytes and hypoxia of centrilobular hepatocytes caused by sinusoidal obstruction by macrophages, combine to injure hepatocytes, causing loss of function and liver failure in alcoholic hepatitis. The epigenetic changes that develop in ballooned hepatacytes lead to preneoplastic hepatocyte formation and development of hepatocellular carcinoma. This hypothesis has been formulated on the basis of preliminary data produced in the applicant's laboratory. The rationale for the proposed research is that understanding the fundamental mechanism of liver injury in alcoholic hepatitis will foster new and more effective treatments for alcoholic hepatitis in which cell cycle arrest is reversed to normal;obstructing macrophages are removed from the sinusoids and balloon cell degeneration is prevented. Guided by the strong preliminary data, this hypothesis will be tested by pursuing three specific aims. 1) Determine the mechanism of cell cycle arrest caused by p21 induction;2) determine the 4 types of macrophages obstructing the sinusoids that cause centrilobular hypoxic injury, and 3) determine the epigenetic transformation that characterizes balloon cell degeneration of hepatocytes. The approach is innovative primarily because it utilizes new technologies described above, developed in the applicant's laboratory, enabling for the first time, the direct study of liver biopsies from patients with alcoholic hepatiis. The proposed research is significant because it is expected that when the mechanisms involved in alcoholic hepatitis are understood it will be possible to design therapies that are life saving with major cost savings that are currently expended in the treatment of alcoholic hepatitis.

Public Health Relevance

The proposed research is relevant to public health because the discovery of key components of the pathogenesis of alcoholic hepatitis will be determined by directly analyzing the molecular pathology of liver biopsies from alcoholic patients. Thus the proposed research is relevant to the part of NIH's mission that pertains to developing fundamental knowledge that will help to reduce the burdens of alcoholic liver disease.

Agency
National Institute of Health (NIH)
Institute
National Institute on Alcohol Abuse and Alcoholism (NIAAA)
Type
Research Project--Cooperative Agreements (U01)
Project #
5U01AA021898-02
Application #
8603217
Study Section
Special Emphasis Panel (ZAA1-JJ (07))
Program Officer
Orosz, Andras
Project Start
2013-01-10
Project End
2017-12-31
Budget Start
2014-01-01
Budget End
2014-12-31
Support Year
2
Fiscal Year
2014
Total Cost
$189,109
Indirect Cost
$46,026
Name
La Biomed Research Institute/ Harbor UCLA Medical Center
Department
Type
DUNS #
069926962
City
Torrance
State
CA
Country
United States
Zip Code
90502
Uthaya Kumar, Dinesh Babu; Chen, Chia-Lin; Liu, Jian-Chang et al. (2016) TLR4 Signaling via NANOG Cooperates With STAT3 to Activate Twist1 and Promote Formation of Tumor-Initiating Stem-Like Cells in Livers of Mice. Gastroenterology 150:707-19
Masouminia, M; Samadzadeh, S; Mendoza, A S et al. (2016) Upregulation of autophagy components in alcoholic hepatitis and nonalcoholic steatohepatitis. Exp Mol Pathol 101:81-8
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French, S W; Mendoza, A S; Peng, Y (2016) The mechanisms of Mallory-Denk body formation are similar to the formation of aggresomes in Alzheimer's disease and other neurodegenerative disorders. Exp Mol Pathol 100:426-33
Liu, Hui; French, Samuel W (2016) Mallory Denk Body Formation in Alcoholic Hepatitis: The Pivotal Role of Interleukin-8 Signaling. Clin Microbiol 5:
Mendoza, Alejandro S; Dorce, Jacques; Peng, Yue et al. (2015) Levels of metacaspase1 and chaperones related to protein quality control in alcoholic and nonalcoholic steatohepatitis. Exp Mol Pathol 98:65-72
Liu, Hui; French, Barbara A; Nelson, Tyler J et al. (2015) IL-8 signaling is up-regulated in alcoholic hepatitis and DDC fed mice with Mallory Denk Bodies (MDBs) present. Exp Mol Pathol 99:320-5
Shen, Hong; French, Barbara A; Tillman, Brittany C et al. (2015) Increased DNA methylation in the livers of patients with alcoholic hepatitis. Exp Mol Pathol 99:326-9
French, S W (2015) How to prevent alcoholic liver disease. Exp Mol Pathol 98:304-7
Liu, Hui; French, Barbara A; Li, Jun et al. (2015) Altered regulation of miR-34a and miR-483-3p in alcoholic hepatitis and DDC fed mice. Exp Mol Pathol 99:552-7

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