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"The role of Glutamine synthetase in Liver Failure: Molecular, Functional and Therapeutic modulation"

Objectif

"The treatment of HE is an unmet need. Ammonia is the central target of therapy but there are no interventions that have been shown to reduce ammonia predictably in liver failure. The main reason for this lack of a proven therapy is because of a lack of understanding of the regulatory pathways involved. Our proposal provides an innovative and original approach to try and understand one of the key regulatory pathways of ammonia metabolism, glutamine synthetase (GS). My proposal will bring together several investigators who have state-of-the-art knowledge and expertise.
The aim of the current proposal is to define the role of GS in liver failure and its potential as a therapeutic target for HE and other associated complications of liver disease including infection. Current therapies for HE fail to address the underlying problem of hyperammonaemia and a recent Cochrane review has suggested that well-established management strategies for HE including lactulose may not improve survival. The novel approaches to the problem we will use are: study of multiple organ enzyme function using a systems approach in disease; use of proteomic aproach to understand GS post-translational modifications; use of GS KO mice to understand the role of muscle GS; use of gene therapy approaches to reconstitute GS; if we prove during this study that gene therapy to increase muscle GS has potential to decrease hyperammonaemia and slow the progression of liver disease, we will have a potential therapy for HE which can enter therapeutic trials in the clinics."

Appel à propositions

FP7-PEOPLE-2010-IEF
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Coordinateur

UCL Elizabeth Garrett Anderson Institute for Women’s Health
Adresse
Gower Street
WC1E 6BT London
United Kingdom
Type d’activité
Higher or Secondary Education Establishments
Contribution de l’UE
€ 271 636,80
Contact administratif
Greta Borg-Carbott (Ms.)