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Financements ANR: une moisson de succès

Trois projets d'IINS-Bordeaux ont été sélectionnés par l'ANR

Le 11 janvier 2018



Suite à l'Appel à projets 2017  transnationaux pour la recherche sur le dysfonctionnement synaptique dans les maladies du système nerveux central dans le cadre de l’ERA-NET NEURON
Résultats 3 équipes IINS:
Christophe Mulle (coordinateur), Valentin Nagerl (coordinateur) et Daniel Choquet (partenaire).

- MISST for Multi-scale investigation of synaptic dysfunction after stroke: Valentin Nägerl, Project Coordinator et Jérôme Badaut du Brain Molecular Imaging group , INCIA  signe d'une belle coopération scientifique à travers le Neurocampus !

 pour : 1.4M Euro
Valentin U.Nägerl (FR)
Nikolaus Plesnila (DE)
Jérôme Badaut (FR)
Leszek Kaczmarek (PL)
Javier Defelipe (ES)
Baiba Jansone (LV)

- KARTLE - Targeting aberrant KAinate Receptors in Temporal Lobe Epilepsy: Christophe Mulle, Project Coordinator
Christophe Mulle (FR)
Valérie Crepel (FR)
Dirk Grimm (DE)
Bernard Pirotte (BE)

 - TREAT-SNGAP for Synaptic Dysfunction in Intellectual Disability Caused by SYNGAP1. Translational Research to Develop Human Models and Advance Pharmacological Treatments. Daniel Choquet as Partner.
Àlex Bayés (ES)
Oliver Brüstle (DE)
Daniel Choquet (FR)
Jacques Michaud (CA)
Barbara Treutlein (DE)

Résumé pour projet MISST 
Each year about 15 million people suffer a stroke worldwide, a disorder typically caused by lack of blood supply to the brain. Many patients survive a stroke acutely, but are struck with life-long disabilities like paralysis, loss of speech, depression, loss of memory, and eventually dementia resembling Alzheimer’s disease. While many lives were saved in recent years due to improved emergency and hospital care for acute stroke, therapeutic options for the chronic consequences of stroke are still missing. The main reason for this unfortunate situation is that we still do not know how the brain reacts to a stroke in the long-term and how these changes are linked to long-term disabilities which usually affect patients for their entire remaining life. The current application brings together the best and most experienced European researchers specialized in synapses, the structures responsible for communication between neurons, and experts in experimental stroke research. This unique consortium of excellence aims to investigate how a stroke in one brain region may affect the function of the whole brain and how these remote and chronic changes after stroke may be manipulated in such a manner that neurological dysfunction may be reduced or even partially or fully restored. Hence, the ultimate aim of the current consortium is to determine the underlying causes of chronic stroke and to pave the way for the development of effective cures. In order to achieve this goal the current group of European scientists will use novel animal models of chronic stroke and investigate tissue from stroke patients with highly innovative imaging technologies such as super-resolution microscopy and high-resolution whole brain and single neuron 3D reconstruction. First we aim to characterize and understand the degeneration of synapses in brain areas far away from the injury induced by stroke in mice and man. Finally, we aim to use this knowledge to evaluate novel therapeutic concepts for the restoration of synaptic function thereby developing novel treatments for chronic stroke.


Résumé pour KARTLE
In humans, the predominant form of epilepsy - a chronic brain disease whose hallmarks are disturbed activity of nerve cells and recurrent seizures - is called temporal lobe epilepsy or TLE. Unfortunately, forty percent of all TLE patients do not respond well to the current generation of pharmaceutical drugs, thus creating an urgent need for novel therapeutic and clinically relevant approaches. Here, we aim to fill in this critical gap, by expanding on our data that a certain type of cell surface molecules (aberrant synaptic kainate receptors, KARs) markedly contribute to epileptiform activity in TLE patients within a specific region of the brain (dentate gyrus [DG], located in the hippocampus area). The central goal of our project is therefore to design and validate two parallel strategies to target aberrant synaptic KARs, in order to inhibit their activity and thereby alleviate the disease symptoms in TLE patients. In the first strategy, we will devise and characterize new pharmacological agents that selectively target and block aberrant synaptic KARs, and will then study their anti-epileptic activity in mouse models of TLE. In the second strategy, we will exploit a cellular mechanism of gene silencing called RNA interference (RNAi) to achieve the same goal, i.e., to remove aberrant syanptic KARs. To efficiently and specifically deliver the molecules inducing anti-KAR RNAi to DG cells, we will engineer gene transfer vehicles based on non-pathogenic Adeno-associated viruses (AAV). Identical to the first strategy, these new AAV/RNAi vectors will then also be tested for anti-KAR activity in mouse models of TLE. Finally, we will additionally validate the best candidates from both strategies in hippocampal tissues that were surgically extracted from TLE patients. As a whole, our project will extend pre-clinical studies in cells and animals to pathophysiologically most relevant human epileptic tissue, which should pave the way for future clinical translation of our innovative approaches.

Résumé pour TREAT-SNGAP
Synapses allow communication between neurons and are also the site for storing sensorial information. It is for this reason that synapses are very important in learning and memory. Recent biomedical research has shown that synaptic dysfunction is at the centre of many brain disorders, especially in conditions where cognitive abilities are impaired, such as intellectual disability (ID) or autism spectrum disorders. The human SYNGAP1 gene encodes a protein that is highly enriched at brain synapses. Recent genetic studies have shown that mutations in SYNGAP1 cause ID. Actually, SYNGAP1 mutations could account for up to 1% of all ID cases, affecting thousands of people worldwide. Basic research studies using mice deficient for SYNGAP1 have shown that, indeed, a synaptic dysfunction is importantly contributing to ID. Nevertheless, there is still no efficient treatment for kids with this disorder. It is thus necessary that we understand in great level of detail the alterations occurring at the synapse if we want to develop SYNGAP1 deficiency treatments. Using mouse models we have studied proteomic alterations found at the synapse of SYNGAP1 deficient animals. This research has allowed us to propose four candidate drugs that we think might correct synaptic alterations, potentially improving this condition. Now we want to actively investigate the effect of these drugs in SYNGAP1 deficiency. As nowadays we have the capacity to develop neurons from human skin or blood cells, we will, for the first time, directly study human neurons obtained from SYNGAP1 patients. These human neurons will also be used to investigate the validity of mouse findings in a human research system. The ultimate goal of TREAT-SNGAP is to identify new strategies to treat ID caused by SYNGAP1.