HE&GS

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

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 Obiettivo del progetto (Objective)

'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.'

Introduzione (Teaser)

Hepatic encephalopathy (HE) is a complex disorder with gradual impairment in the mental performance and reactions to external stimuli. Understanding of the regulatory pathways involved in the HE would ultimately lead to a more effective therapy.

Descrizione progetto (Article)

Inefficient clearance of ammonia by the liver due to liver disease leads to HE. Cirrhosis is the major cause of chronic liver dysfunction and affects 1 million Europeans and 5.5 million Americans. At present, there are no interventions that have been shown to reduce ammonia in liver failure.

The enzyme glutamine synthetase (GS) produces the amino acid glutamine and is the key regulator of ammonia metabolism. The EU-funded Marie Curie 'The role of glutamine synthetase in liver failure: molecular, functional and therapeutic modulation' (HE&GS) project aimed to define the role of GS in liver failure and its therapeutic potential for HE treatment.

As an initial step, researchers obtained mouse knockout models in collaboration to test the importance of selective deficiency of GS in the muscle. The animals lacking muscle GS had significantly greater brain swelling and liver injury that was associated with more severe hepatic inflammation. This happens due to the greater migration of bacteria from the gut into the blood stream.

Muscle depletion is frequently encountered in patients with cirrhosis and together with malnutrition is an independent prognostic factor for survival. Using mass spectrometry, researchers identified that the animals lacking muscle GS had more severe oxidative stress in the muscle proteins. These results explained why the lack of GS function in the muscle produced deficiency in energy storage and muscle loss.

Project data suggested that the reconstitution of GS in the muscle is likely to be an important therapy. Researchers successfully developed a viral vector for safe delivery of a GS expressing construct to the muscle. Using this approach, it is now possible to produce a virus that can be used for the study of muscle GS replacement.

The results of this project have allowed further clarification of the important role of muscle GS, the mechanisms of the reduction of GS function and their effects in liver failure. Further development of the novel gene therapy constructs will lead to a new approach for patients with liver failure and HE.