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Examination of the mGluR-mTOR Pathway for the Identification of Potential Therapeutic Targets to Treat Fragile X

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Annual rept. 30 Sep2 012-29 Sep 2013

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Fragile X Syndrome FXS is a single gene disorder caused by loss of FMR1 gene function. This disease leads to cognitive impairment and is the most common genetic cause of autism, accounting for 2- 6 of all diagnosed cases Hagerman et al 2008. In previous studies of a Drosophila model for FXS, we identified pharmacological treatments that rescued phenotypes relevant to this syndrome such as social, neuroanatomical and cognitive deficits McBride et al., 2005 Choi et al., 2010. These results have been translated to the mouse model of FXS leading to the impetus to initiate clinical trials with Fragile X patients Yan et al., 2005 Dolen et al., 2007 de Vrij et al., 2008 Choi et al., 2011. The fact that clinical trials of two distinct compounds identified in flies and tested in mice have reported some level of efficacy highlights the relevance of Drosophila and mouse- based disease modeling to identify potential treatments for developmental brain disorders and other diseases Berry- Kravis et al., 2008 Berry- Kravis et al., 2009 Jacquemont et al., 2011. Our objective is to fully explore a recently defined link between metabotropic glutamate receptor mGluR signaling and the mTOR pathway, two pathways that have been previously examined in Fragile X without having the pathways involving these two proteins dissected in depth Banko et al., 2006 Ronesi and Huber, 2008 Sharma et al., 2010. In preliminary testing of this link we have identified additional pharmacologic treatments that rescue either the cognitive andor social interaction deficits displayed by the Drosophila model TAJ and SmcB, unpub.. Our objective is to fully explore the link between these two pathways to identify as many potential targets for pharmacological intervention of FXS.

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  • Psychology
  • Genetic Engineering and Molecular Biology
  • Medicine and Medical Research

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