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.

Identification of circulating miRNAs in drinkers associated with risk for alcoholic liver cirrhosis

Primary supervisor: Devanshi Seth

Despite the recognition of alcohol as an important cause of liver cirrhosis, the molecular and cellular mechanisms of liver injury remain unclear. There is evidence that genetic risk factors may predispose drinkers to develop cirrhosis but these factors do not entirely explain the variability observed in this disease. Regulation of genes can occur through epigenetic mechanisms such as miRNAs.

Recent works in animal models of alcoholic liver injury suggest that miRNAs may be important players in alcohol-induced gut permeability, Kupffer cell activation, oxidative stress, inflammation and other pathogenic processes (Bala et al Int J Hepatol 2012). This project aims to profile and identify miRNAs associated with Alcoholic Liver Cirrhosis (ALC) in patients.

HYPOTHESES: miRNAs are important epigenetic regulators in the development of Alcoholic Liver Cirrhosis.

AIMS

1. To discover differentially expressed (DE) miRNAs in ALC by global miRNA profiling

2. To replicate miRNAs discovered in aim 1 in independent cohort through focussed custom array

3. To develop gene networks associated with/regulated by miRNAs (Ingenuity)

4. To identify miRNAs associated with the risk of ALC through regression analysis with clinical data

 

METHODS: Blood/serum from clinically characterised Controls (heavy drinkers without ALC) and Cases (heavy drinkers with ALD) matched for age, gender, alcohol consumption, are available from previous multinational GenomALC study. We have established methods for RNA (total, miRNA enriched) isolation (Qiagen), global and custom array miRNA profiling (TaqMan OpenArray ultra-high content platform for quantitative real-time PCR (qPCR)). Statistical analysis will identify differentially expressed miRNA in ALC as potential diagnostic markers. Regression analysis for association between clinical phenotype and miRNAs will identify risk factors for ALC.

INNOVATION

This study will utilize hundreds of samples already genotyped by GWAS-SNP. miRNA profiling in this cohort has the potential to combine knowledge of genetic with epigenetic risk factors in order to understand the molecular pathogenesis of ALC.

EXPECTED OUTCOMES

Identification of miRNA will lead to discovery of novel regulatory elements in ALD pathogenesis.

The creation of global miRNA profiles will help build regulatory networks in human ALD.

Results from this project combined with our multi-national GenomALC Consortium on genetics of ALC will significantly contribute towards much needed understanding of this disease.


Discipline: Pathology
Co-supervisors: Mugdha Joglekar, Anandwardhan Hardikar
Keywords: Alcohol, Epigenetics, Liver Disease
Contact: