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Cellular Mechanisms and Therapies for Rett Syndrome

Obiettivo

Rett Syndrome (RTT) is an X-linked neurodevelopmental disorder and the leading known genetic cause of autism in girls. RTT is characterized by normal early development followed by cognitive, motor and language regression. Mutations in the X-linked MECP2 (methyl-CpG binding protein 2) gene account for at least 80% of RTT cases. In mouse models, CNS-specific deletion of Mecp2 is sufficient to cause Rett-like symptoms. In patients as well as in the mouse models, the involved CNS circuits do not show atrophy but rather remain in an immature state. Although there is no known cure for RTT, gene therapy in MeCP2 mutant mouse models has proven effective in rescuing the phenotype, showing that this neurological condition may be reversible. A therapy for human use might arise from identifying an agent capable of stimulating brain circuit maturation if applied systemically. This proposal identifies such an agent in the form of insulin-like growth factor 1 (IGF1), a pleiotrophic growth factor in the brain. IGF1 specifically targets many of the systems and features impaired in RTT such as cell size and dendritic arborization, synapse maturation, the gabaergic system, hippocampal learning and plasticity, and cognitive abilities. IGF1 is capable of crossing the blood-brain barrier and has already been approved for human clinical trials. IGF1 thus offers a means to reverse the RTT phenotype by engaging key molecular pathways to stimulate synaptic maturation, in a format that is more amenable to therapeutic administration to RTT patients. This proposal aims to clarify the neurobiology of MeCP2 protein in MECP2 mutant animal models and to test the efficacy of IGF1 and its derivates for RTT therapy. Successful therapies for RTT have significant implications for other autism spectrum and neurodevelopmental disorders.

Invito a presentare proposte

FP7-PEOPLE-2009-RG
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Coordinatore

THE PROVOST, FELLOWS, FOUNDATION SCHOLARS & THE OTHER MEMBERS OF BOARD, OF THE COLLEGE OF THE HOLY & UNDIVIDED TRINITY OF QUEEN ELIZABETH NEAR DUBLIN
Contributo UE
€ 50 000,00
Indirizzo
COLLEGE GREEN TRINITY COLLEGE
D02 CX56 DUBLIN 2
Irlanda

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Regione
Ireland Eastern and Midland Dublin
Tipo di attività
Higher or Secondary Education Establishments
Contatto amministrativo
Deirdre Savage (Ms.)
Collegamenti
Costo totale
Nessun dato