Neurodegenerative processes of ageing and disease nPad.
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Transcript of Neurodegenerative processes of ageing and disease nPad.
Neurodegenerative processes of ageing and disease
nPad
• Identify key genes and proteins involved in triggering neurodegeneration in vivo.
• Examine contribution of neuronal, synaptic and glial dysfunction to neurodegeneration.
• Assess biomarkers of cognition and behaviour capable of tracking neurodegeneration.
• Study impact of stress, infection and age on neurodegenerative processes.
• Identify common and distinct molecular mechanisms underlying neurodegeneration.
• Develop strategies for blocking neurodegenerative processes.
Aims of the consortium
The PeopleUniversity of EdinburghThe Roslin Institute & R(D)SVS: Prof Jean Manson, Dr Rona Barron, Prof Tom Freeman, Dr Andrew Gill, Dr Barry McColl , Prof Kim Summers, Dr Tom Wishart Centre for Cognitive and Neural System: Prof Richard Morris, Dr Emma Wood Centre for Neuroregeneration: Prof Peter Brophy, Dr Liliana Minichiello, Dr Karen HorsburghHuman Cognitive Neuroscience, Psychology: Prof Sergio Della Sala Centre for Integrative Physiology: Prof Tom Gillingwater, Prof Richard Ribchester, Prof David Wyllie, Prof Giles Hardingham, Dr Mandy JacksonCentre for Clinical Brain Sciences: Prof Siddharthan Chandran, Prof Seth Grant, Prof Joanna WardlawCentre for Regenerative Medicine: Prof Charles ffrench Constant (CfC)The National Creutzfeldt-Jakob Disease Research and Surveillance Unit: Prof James Ironside, Prof Richard Knight , Prof Robert Will Centre for Cardiovascular Sciences: Prof Jonathan Seckl , Prof Megan C Holmes, Dr Joyce Yau Centre for Cognitive Ageing and Cognitive Epidemiology: Prof Ian Deary, Prof John Starr University of St Andrews School of Biology: Prof Frank Gunn-Moore
The ExpertiseIdentifying and analysing disorders of the brain, spinal cord, eye, peripheral nervous system and muscle using a range of morphological, molecular, behavioural and functional approaches.
The Tools Microscopy (including confocal and electron microscopy), Neurophysiology (including in vitro electrophysiology and synaptic physiology), Molecular biology (including proteomic and gene expression screens), mouse behavioural models of learning and memory
Additional Resources•Access to unique human ageing cohorts •Access to banks of human tissues from normal individuals and patients with a wide variety of disorders•Current strategic award bid to Wellcome for a major centre for Comparative Pathology
• Candidate genes from studies of human patient cohorts and mouse models of neurodegenerative disease to define targets for knockouts.
• Examination of publicly available gene expression data sets to discover genes that are expressed in neurons and are important in synaptic function.
• Evidence that chosen genes may be important in neurodegenerative disease from human studies or mouse models, in particular those with an identified role at the early stages of disease.
Rationale for prioritising genes
injectionterminal disease
0 50 100 150 200 250
abnormal PrP loss of synapses& axon terminals, abnormalLTP
gliosis neuron loss
clinical disease, neuronal
dysfunction
150d.p.i
30d.p.i
control
98dpi
126dpi
Jan Fraser and Debbie Brown
Dissecting the early events in neurodegeneration
Pre-synaptic
Post-synaptic
Tom Gillingwater
126dpi
Tom Gillingwater
microglia astrocytes
neurones
Multiple cell types respond to disease
Neuronal cells
Cell division and protein synthesis
Astrocytes
Macrophages
Connective tissue cells
Kim Summers
We expect the knockouts of targets described here will alter the early part of the process of neurodegeneration
Our phenotypic analysis will be designed to use the full range of expertise within the consortium to analyse neurodegenerative progression through:
•studies on behavioural phenotype induced by the knockout;
•examining the influence of the knockout on acute or chronic neurodegenerative process;
•analysing phenotypes arising from ageing the knockout mice with and without well characterised stressful interventions (model systems).
Our approach
1. Production and distribution of mice
2. Pathologic analysis
3. Data gathering and distribution
4. Pilot studies
5. Other studies
Funding strategy
Atp1b1Atp2a2AvpCacna1aClstn1CluCnpGnao1Igf1rMaptMbpNpas4Spnb3Taglin3
Chmp2b Igf1 VapbCacna1b Cacna2d1 Col4a3 Comt Dapk1 Dtnbp1 Gabarapl1 Gabarapl2Htra1MthfrPrkar2bVcp
Acta2 Adamts10 Als2 Atxn3 Cd2apEpha1Pink1Slc1aSod1Fbxw7Mapk9Ndrg4Rims3
Genes of interest to the consortium in production