Significance of Osteopontin and its splice variants in alcoholic liver disease

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Summary

Alcohol induced Opn and Opn isoforms play a role in the progression of alcoholic liver injury mediated via integrin and non-integrin receptor binding.

Supervisor(s)

Dr Devanshi Seth

Research Location

Camperdown - Centenary Institute

Program Type

Masters/PHD

Synopsis

We described the global hepatic transcriptome in human ALD1, identified increased Opn, CD44, and integrin v and that acute exposure to ethanol increased Opn in a mouse model and in hepatocyte cell cultures.2 Preliminary data demonstrates biologically significant variations in functional activity between isoforms (Opn-A, Opn-B and Opn-C) for cell growth and cell migration. These results support the notion that Opn variants have diverse activities in ALD. Hypothesis: Alcohol induced Opn and Opn isoforms play a role in the progression of alcoholic liver injury. Research Plan: This project will investigate the mechanisms of Opn action in in vitro and in vivo alcohol models and characterize the functional activities of Opn variants by studying the effect/role of: • Alcohol on Opn, Opn isoforms and Opn receptor mediated signalling. • Opn isoforms in hepatic cell culture models using functional assays. • Opn knockdown on the functions of Opn variants in cell culture models. • Acute alcohol in Opn knockout (Opn -/-) mice. Significance: The outcome would greatly extend understanding the role of Opn, its splice variants, and signalling in ALD, lead to the development of novel diagnostic molecules with therapeutic implications for liver disease. 1. Seth et al. Alcoholism: Clinical & Experimental Research. 30 (9): 89A:336. 2. Seth et al. J Hepatol 2006, 45:306-320.

Additional Information

Following techniques will be used in the project:

  • In vitro and in vivo: cell lines, primary cell culture, animal handling, alcohol administration
  • RNA and protein: Q-PCR, immunohistochemistry, Western blotting, flow cytometery, ELISA, proteomics.
  • Knockdown studies: RNAi, antibody inhibition, Opn -/- mouse
  • Cell signalling: immunoprecipitation, anti-phospho and kinase assays
  • Functional assays: cell-growth, cell-migration, chemotaxis
  • Electron microscopy, live cell imaging
  • Animal handling and alcohol administration
Dr Seth has expertise in alcohol related liver injury, alcohol mouse models, molecular biology, functional assays and data analysis. She has supervised and co-supervised PhD students (University of Western Australia, University of Sydney) and Honours students (USYD). Prof Paul Haber is well known in the area of alcoholic liver injury and will provide clinical expertise to this project. Dr Gopal Kundu, Principal Scientist, Transduction Signalling Unit, National Centre for Cell Science, Pune, India, is a current collaborator and will bring in expertise on cell signaling for this project. The project may require travel to his laboratory for technology transfer.

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Keywords

Alcoholic liver disease, alcoholic hepatitis, alcoholic steatosis, liver injury, hepatic fibrosis, Osteopontin, acute alcohol, Cell signalling, chemotaxis, RNAi, knockdown, blocking antibody, Proteomics, Liver & hormonal disorders, Therapeutics & adverse drug effects, Health & lifestyle, Human body

Opportunity ID

The opportunity ID for this research opportunity is: 251