The ASPIRE Path in Molecular Medicine

The goal of my project is to develop potential treatments for Rett syndrome (RTT), a neurodevelopmental disorder caused by mutations in the Methyl CpG Binding Protein 2 (MECP2) gene that affects 1 in 10,000 female births. These children show developmental regression starting at 6 to 18 months of age with loss of social and motor abilities, respiratory dysfunction, and repetitive behaviors. Despite many MeCP2 studies, there remains limited treatments for RTT. Our lab has shown that Grm7, the gene encoding metabotropic glutamate receptor 7 (mGlu7), is reduced in RTT mouse models and that mGlu7 is reduced in RTT patient samples. Interestingly, various endogenous microRNAs can directly affect GRM7 levels in other neurological disorders and specifically microRNA 15a was upregulated in postmortem cortices of RTT patients. Therefore, I will design an antisense oligonucleotide that blocks the binding of microRNA 15a to GRM7 in neuron cultures and in RTT mouse models. In addition, I will evaluate the effectiveness of novel mGlu7 positive allosteric modulators to increase mGlu7 expression and correct behavioral phenotypes in Rett mice. I plan on investigating mechanisms of reduced mGlu7 expression in RTT by using patient brain samples and look forward to further developing that aspect.