Biologie et Pathologie du Neurone
Responsable Christian NERI
The aim of this project is to advance our understanding of the role and therapeutic value of key neuron-survival mechanisms during the early phases of the pathogenic process in neurodegenerative disease (ND) and to transfer this knowledge to clinical research. Secondary aims include i) the development of a powerful open-access environment for knowledge discovery in ND and ii) the continuation of a strategic drug-discovery program with AFM for combating muscular and motor neuron disease. Our hypothesis is that pathways that are essential for longevity/cell-survival such as the FOXO pathway may be key to neuronal resistance (i.e. ability of individual neurons to resist disease over the long term), thus having strong therapeutic potential. Our hypothesis is also that studying Huntington’s disease (HD), a model disease, may boost our understanding of the role of neuron resistance in ND. The questions we address are i) what are the effects of abnormal neurodevelopmental signalling on the regulation of FOXO-dependent neuronal-resistance mechanisms in HD, and would this explain the variability of HD? Would this knowledge provide ways to slow-down HD progression and new avenues for therapeutic discovery in other degenerative diseases? We will pursue 3 objectives including 1. To identify the FOXO-dependent neuronal-resistance mechanisms that are impaired by abnormal neurodevelopmental signalling in HD using human iPS cells (FOXODIRECT), 2. To implement infrastructure for system-level knowledge discovery in ND (Biogemix), use it for the project and promote its use for other diseases. 3. To pursue drug screening/repositioning for therapeutic discovery in diseases of interest in the project (Translation). The main deliverables include i) advanced knowledge on neuronal resistance in HD in the larger context of system-level modelling and ii) a portfolio of validated targets for neuron preservation (HD), and a portfolio of validated lead compounds (diseases studied with AFM), which will provide a breadth of investigation that links basic biology, through systemic and bioinformatic approaches to translational research at the Institute of Longevity at Charles Foix hospital

B2A UMR 8256 @Février 2014