Principal Investigators


Professor G Mallucci

Institution


MRC Toxicology Unit

Contact information of lead PI


Country


United Kingdom

Title of project or programme


In vivo models of disease and toxicity in the nervous system

Source of funding information


MRC

Total sum awarded (Euro)


€ 9,477,939

Start date of award


01/09/2011

Total duration of award in years


5.0

The project/programme is most relevant to:


Prion disease | Neurodegnerative disease in general

Keywords


Research Abstract


Neurodegenerative diseases, such as Alzheimers, Parkinsons, Huntingtons disease and amyotrophic lateral sclerosis, have enormous clinical and economic impact world wide. Irrespective of the final pattern of clinical symptoms, they all are caused by an irreversible loss of neurons, which cannot be cured. But before neuronal death, there are neuronal dysfunction and synaptic impairment, which potentially can be treated.||my background is in prion diseases, modelling these in transgenic mice to look at mechanisms of neurotoxicity and developing new therapeutic approaches. In particular, I focused on the changes of early prion neurotoxicity and recovery from it. This new programme uses mouse models to understand the early molecular events in prion and other neurodegenerative diseases, looking in parallel at potential therapeutic targets for prevention of neuronal dysfunction and death.||Our main aims are to:|1. Characterise pre-degenerative neuronal changes.|2. Understand what triggers ultimate commitment to death in a malfunctioning neuron.|3. Define the molecular targets and the temporal window for functional recovery.||Initially, these questions will be addressed using our established mouse model of prion disease where early pathology is associated with a pivotal point in neuronal survival/death, and there is potential for recovery. We will use molecular biological, biochemical and neurophysiological techniques, as well as neuronal imaging in culture and in vivo to characterise the underlying cellular and synaptic changes, including alterations in signalling pathways and ion channels.||The broader aims of the programme are:|4. to generate new mouse models to look at individual pathways implicated in early dysfunction and their effect on neuronal function and death.|5. to address therapeutic strategies for the treatment of neurodegeneration.

Lay Summary


One of the greatest challenges in neuroscience, and to public health, is how to treat neurodegenerative diseases. These diseases involve the death of brain cells. When they are lost, the functions they control memory, movement and emotion are also irreversibly lost. In order to treat these disorders, we need to understand why brain cells degenerate and die. Most importantly, we need to understand the earliest stages of this process as this gives us the greatest chance of intervening to prevent cell death. I previously made a mouse model of prion disease in which early degeneration is reversible. In these mice, early structural changes in brain cells lead to changes in behaviour, memory and electrical signalling, very like early changes seen in human neurodegenerative disorders. Using either special genetic techniques we were able to reverse this process. The structural, behavioural and memory changes were all reversed and instead of dying, the mice recovered and lived a normal lifespan. We aim to understand the processes that control this recovery and use this to find targets for treating neurodegeneration.

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