Vascular Adhesion protein-1 (VAP-1) and the development of inflammation in non-alcoholic steatohepatitis (NASH). (360G-Wellcome-083684_Z_07_Z)
Non-alcoholic steatohepatitis (NASH), a manifestation of the metabolic syndrome, is a leading cause of liver cirrhosis in the developed world. The adhesion molecule vascular adhesion protein-1 (VAP-1), which promotes lymphocyte recruitment to liver, is a semicarbazide sensitive amine oxidase (SSAO). ). VAP-1/SSAO deaminates primary amines resulting in the generation of aldehyde, ammonia and H2O2 which activate NFkB-dependent chemokine and adhesion molecule expression. Blockade of SSAO signific antly reduces lymphocyte trans-endothelial migration. A soluble form of VAP-1 is shed from liver endothelium and circulating levels are elevated in patients with alcoholic liver disease and diabetics with vascular disease and hyperlipidaemia. Thus VAP-1/SSAO might be implicated in hepatocyte steatosis and in amplifying NFkB-driven inflammation and leucocyte recruitment during the development of steatohepatitis. I propose that VAP-1 blockade will reduce oxidative stress, NFkB-driven inflammat ion and leucocyte recruitment in steatohepatitis. I will determine whether patients with NASH have increased serum VAP-1 and SSAO activity and if so whether this is associated with increased binding of leucocytes to liver endothelium in vitro. I will then use mouse models to investigate the role of VAP-1/SSAO in vivo. These studies may suggest novel therapeutic strategies for the treatment of NAFLD.
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Grant Details
Amount Awarded | 229729 |
Applicant Surname | Claridge |
Approval Committee | Clinical Interview Committee |
Award Date | 2007-12-06T00:00:00+00:00 |
Financial Year | 2007/08 |
Grant Programme: Title | Research Training Fellowship |
Internal ID | 083684/Z/07/Z |
Lead Applicant | Dr Lee Claridge |
Partnership Value | 229729 |
Planned Dates: End Date | 2011-06-01T00:00:00+00:00 |
Planned Dates: Start Date | 2008-06-02T00:00:00+00:00 |
Recipient Org: Country | United Kingdom |
Region | West Midlands |
Sponsor(s) | Prof David Adams |