VEGFALS · Therapeutic role of different VEGF members on neuron and muscle degeneration

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Project objective

Recent evidence suggests that members of the VEGF family may be of therapeutic value for neurodegenerative disorders, such as amyotrophic lateral sclerosis (ALS). Indeed, VEGF administration significantly improved the clinical outcome of animal models of A LS.To further define the role of VEGF in motoneuron degeneration and in preparation of clinical trials, this project will investigate whether the expression of VEGF by the skeletal muscle might affect muscle atrophy and neuromuscular junction integrity in rodent models of ALS (SODG93A rats and mice).This hypothesis will be investigated by inter-crossing SODG93A with transgenic mice over-expressing or lacking VEGF in the skeletal muscle. Alternatively, in vivo VEGF gene transfer to skeletal muscle fibers will be obtained by using vectors based on the Adeno-Associated Virus (AAV).These models will represent a powerful tool to investigate whether muscle-derived VEGF can influence disease progression by maintaining muscle integrity or by inducing muscle regeneration and/or motor unit enlargement through axonal sprouting.In addition, further work will be focused on the role of a novel VEGF homologue, VEGF-B, and its receptor Flt-1, in motoneuron degeneration, based on the observation that ALS mice lacking VEGF-B display an aggravated phenotype.These mice will be therefore employed to determine whether VEGF-B exerts a neuroprotective support to motoneurons, atrophic effect on muscle fibers or a regulatory activity on glial cells.Finally, a possible therapeutic role of VEGF-B in ALS will be explored, by either directly injecting the recombinant protein into the brain ventricles, or by intramuscular injection of AAV-VEGF-B vectors.Collectively, these studies will generate insights with relevant implications to further optimize VEGF-based therapeutic strategies for ALS and other neurodegenerative disorders.

Original text from CORDIS.

Participants

• FLANDERS INTERUNIVERSITY INSTITUTE FOR BIOTECHNOLOGY VZW · ZWIJNAARDECoordinatorBelgium

Links

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