Alcoholic Liver Disease Group, Liver Injury & Cancer

Lab head: Dr Devanshi Seth
Location: Drug Health Services & Centenary Institute

The excessive use of alcohol is widely recognised as a major health and social problem in Australia and worldwide. Alcohol is associated with over 60 medical diseases of which Alcoholic Liver Disease (ALD) causes the most deaths, and is consequently the greatest public health problem. Despite the the increased incidence of other liver diseases, such as hepatitis C (HepC) and fatty liver disease, alcohol is still the most common casue of advanced liver disease in Australia. Indeed, consumption of alcohol further exacerbates HepC as well as non-alcoholic fatty liver disease, and alcoholic cirrhosis is an important cause of liver cancer, the most rapidly rising form of cancer. Importantly, the incidence of ALD is on the rise, especially in the young. To date, there are no specific biomarkers for ALD and treatment remains unsatisfactory, further compounding the burden of liver disease.

 

The key gaps in understanding this disease are: (1) early identification of liver injury via and appropriate biomarker; 92) why only a proportion of chronic excessive drinkers progress to cirrhosis while others drinking to similar levels do not?; (3) what are the molecular, cellular and genetic mechanisms underlying the progression of alcoholic liver disease.

Website: www.genomalc.org
Funding: NIIH; AISRF
Research approach equipment: The current research program that I am leading is a much needed and often neglected but significant area of alcoholic liver disease, investigating factors that increase the risk of disease development in order to develop better treatments for patients. We are doing clinical research on thousands of drinkers worldwide using genomic approaches (transcriptomics, GWAS, epigenetics, miRNA profiling, lipidomics) to build a genetic, regulatory and functional architecture of this disease. We also have in vitro cell culture and mouse models of acute and chronic alcohol and high fat diet in combination with chronic alcohol, recapitulating human settings, to study the mechanisms of alcohol action in liver injury. We identified novel molecules and pathways(osteopontin, annexin 2A, fibrinolysis, plasmin activation) that are being actively investigated. We are also looking at another significant area of liver regeneration, essential for recovery during injury, such as, neo-angiogenesis, role of bone marrow-derived endothelial cells in acute and chronic liver injury and influence of inflammation during injury. This research program is unique in Australia in broadly addressing the gaps in understanding alcoholic liver disease via genetic, cellular and clinical studies for diagnostics and therapy.

To investigate the mechanism/s of SPP1 action in liver injury model of alcohol and high fat diet using SPP1 knockout animals

Primary supervisor: Devanshi Seth

BACKGROUND:

Recent evidence suggests that similar molecular mechanisms may operate in both alcohol and non-alcohol induced liver injury progression. One such mechanism involves Secreted phosphoprotein 1 (SPP1) pathway. We showed for the first time that SPP1expression increased significantly in the cirrhotic lesions in human liver with ALD [1], in vitro cell culture and in vivo mouse model of alcohol [2-4].

Most recently, Honours project from our laboratory in wild type (WT) animals fed high fat diet (HFD) and alcohol identified exacerbated liver injury and increased SPP1 pathway compared to chow-fed and only HFD and alcohol diet. This suggests that SPP1 may be important in furthering HFD and alcohol induced liver damage. This project will study the precise mechanism/s of SPP1 action that has not been defined in a combined HFD and alcohol-induced liver injury.

AIM: To characterise role of SPP1 in alcohol and high fat diet models of liver injury using SPP1 knockout (SPP1 kos) mice.

METHOD: Liver samples from WT and SPP1 kos mice fed chronic alcohol and HFD will be used for studying SPP1 pathway molecules will be determined (Q-PCR, Western blotting, Immunohistochemistry, immunofluorescence, ELISA). SPP1 pathway correlation with extent of liver injury will be evaluated. Changes in fibrogenesis and extracellular matrix (ECM) pathways will be compared between WT and SPP1 kos in order to determine whether or not SPP1 pathway has a generic role in liver injury. The common endpoints for these experiments are expression analysis of SPP1 pathway component and liver injury assesment and functional assays.

 EXPECTED OUTCOMES

  • These experiments will clarify the biological role/s of SPP1 in combination of HFD and alcohol induced liver injury.
  • Identification of SPP1 specific mechanisms/ pathways may lead to the development of a future therapeutic strategy. 

This study has a strong potential to lead to a future PhD.

SIGNIFICANCE: SPP1 seems to be critical in liver diseases as shown from our data in ALD and others in NASH. In addition, anti-SPP1 strategies in other models of liver disease [5] suggest that SPP1 in vivo may be a potential therapeutic target for liver fibrosis.

INNOVATION: Our data suggests a novel mechanism by which SPP1 may play a role in the progression of liver fibrogenesis by altering the plasmin-mediated fibrinolysis and is an important precursor to developing therapeutic strategies for ALD.

REFERENCES: 1.Seth D, J Hepatol 2006; 2. Seth D. Alc Clin Exp Res 2006. 3. Seth D. Alc Clin Exp Res 2007. 4.Seth D. Alc Clin Exp Res 2010; 5.Syn W-K. Hepatol 2010.


Discipline: Infectious diseases and Immunology
Co-supervisors: Susan McLennan
Keywords: Alcohol, Fibrosis, Liver fibrosis
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