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Deciphering the Negr1 interacting network in physiological conditions and in psychiatric and neurodevelopmental disorders.

There are no therapies for the core symptoms of most psychiatric and neurodevelopmental disorders. Compelling evidence indicates that most of these disorders feature aberrant neuronal connectivity. Importantly, the neuronal growth regulator 1 (Negr1) is associated with neuronal connectivity and diverse brain disorders. Thus, a better understanding of how Negr1 exerts its functions may reveal general principles underlying these pathological conditions. Previous results show that Negr1 does not operate as single entity. Negr1 functions by physically interacting with other proteins. In this context, PSYNegrT will investigate the hypothesis that the brain’s Negr1 interacting-protein network is remodeled in psychiatric and neurodevelopmental disorders. The fellow will investigate the role of specific Negr1 complexes in diverse brain disorders and their possible exploitation as drug targets. To this aim, he will identify and characterize the brain’s Negr1 interacting-protein networks by proteomic, biochemistry, and molecular biology studies. Computational and mutagenesis studies will reveal structural features for molecular interactions at the interface between Negr1 and selected partner proteins. This project will thus: i) produce the first exhaustive list of cerebral Negr1-interacting proteins in physiological conditions ii) identify the protein-protein interactions involved in Negr1-mediated pathological effects. With PSYNegrT, the fellow will increase his research skills and expertise in molecular biology and modeling, thus flourishing into an independent group leader. The project will be a breakthrough in our understanding of the causes of diverse brain disorders, and it will reveal certain general principles underlying their pathophysiology. This will facilitate structure-based efforts to design small molecules, peptides, or nanobodies to target Negr1-mediated protein-protein interactions involved in these disorders.

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Amos Fumagalli
Brain Development and Disease
Total budget: 183.473,28€
Total contribution: 183.473,28€