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Final Activity Report Summary - SPIN (Systems proteomics to implement neuroscience)

Acute and chronic neurological diseases are a major cause of death and impair the daily lives of millions of inhabitants in the European Union. The overall economic impact of cerebrovascular disease is estimated to cost the European economy 34 billion a year. Epilepsy and seizure disorders are the most common neurological diseases, affecting almost 1 to 3 % of the population. Neuroprotective treatments could benefit both diseases but, despite research over more than two decades revealing therapeutic targets such as calcium channels and glutamate receptors, findings are not yet translated into the clinic, or have provided limited or disappointing results. The underlying problem may lie in the approach which is currently envisaged in most scientific studies, focussing on a 'one gene at a time' fashion in order to unravel new targets for the generation of new drugs.

The SPIN project chose proteomic approaches to fasten the laborious work to examine the intertwined pathways underlying these diseases. This allowed us to step forward from the 'one gene at a time' approach to a broader, parallel way of understanding. The transfer of knowledge (ToK) fellows Dr Koenig and Dr Fenner transferred knowledge and expertise to identify 'interactomes' of proteins, including Bcl-2 family proteins and 14-3-3 family proteins, using mass spectrometry and protein array-based technologies, with the support of the bioinformatics team led by Dr Achim Treumann. These newly identified proteins were explored by the in vitro and in vivo disease modellers, using primary cultured neurons, organotypic hippocampal slice culture and neurosurgical mouse models, such as stereotactic N-methly D-aspartate (NMDA) lesions, focal cerebral ischemia, intra-amygdala kainate acid injections and mutant SOD1 transgenic mice, all of which were developed during the course of this project.

The gene delivery and protein transfer team subsequently developed new technologies to explore the effect of gene and protein delivery and gene silencing of key candidates in the in vitro and in vivo disease models. This was achieved through the recruitment of Dr Paul Foley and Dr Beau Fenner, specialised in lentiviral delivery systems, and Dr Isabelle Virard, for adeno-associated virus (AAV) based delivery systems, who established a gene transfer and protein delivery unit with the Royal College of Surgeons in Ireland (RCSI) Neuroscience Research Centre, and were trained in in vitro and in vivo neuroscience disease models. Concurrently, the existing team members acquired the technical skills and expertise in gene transfer methods and proteomics methods. The delivery systems were successfully tested and used both in cultured neurons and in vivo.

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