The roles of STAT-1/3 in NASH and liver cancer

Project: Research

Project Details

Project Description

Synopsis:
Obesity is a major driver of liver disease and liver cancer in the developed world. The impact of obesity on liver disease and liver cancer is largely attributable to the increased risk for non-alcoholic fatty liver disease (NAFLD). NAFLD encompasses a broad spectrum of conditions ranging from non-alcoholic fatty liver (NAFL), to the more severe and progressive non-alcoholic steatohepatitis (NASH), a condition that results in fibrosis and if left unresolved, cirrhosis and/or hepatocellular carcinoma (HCC). The molecular basis for the NAFL to NASH transition and the development of HCC in obesity remain unclear.
Our preliminary studies indicate that the oxidation and inactivation of hepatic protein tyrosine phophatases in obesity is accompanied by the promotion of STAT-1/3 signaling and the progression from NAFL to NASH and HCC.
HYPOTHESIS: Oxidative stress in obesity inactivates hepatic PTPs to promote inflammatory & oncogenic STAT-1/3 signaling & the progression from NAFL to NASH & HCC.
We will determine the mechanisms by which STAT-1/3 contribute to NASH/HCC and the therapeutic potential of targeting STAT-1/3 pathways.
SPECIFIC AIMS:
1. To define the role of hepatocyte STAT-1/3 signaling in obesity-associated NASH.
2. To define the role of hepatocyte STAT-1/3 signaling in obesity-associated HCC.
3. To characterise the hepatocyte STAT-1/3 transcriptional targets FGL1, CXCL9 and LCN-2 as non-invasive diagnostic markers for obesity-associated NASH/HCC.
4. To assess the impact of inhibiting STAT-1/3 pathways on NASH and HCC in obesity.
SIGNIFICANCE: Obesity-associated NASH is currently the third leading cause for liver transplantation and is expected to soon surpass hepatitis C as the principal cause for liver transplantation and HCC in the developed world. This proposal will provide significant insight into fundamental processes pertinent to the development of NASH and HCC. Our findings may afford novel opportunities for early diagnosis and treatment.

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Plain English Summary:
Obesity is a major driver of liver disease and liver cancer. Obesity-associated liver disease is the third leading cause for liver transplantation. Liver cancer is one of the world’s deadliest cancers and the third most common cause of cancer death. There are no medications that prevent or effectively treat liver disease and cancer. This proposal will define processes pertinent to the development of liver disease and cancer and identify approaches for their early diagnosis and treatment.
StatusActive
Effective start/end date1/01/1831/12/20