ISRIB as a promising therapeutic for Fragile X syndrome

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PROJECT SUMMARY/ABSTRACT Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by cognitive and behavioral difficulties including intellectual disability, anxiety, hyperactivity, and many other autistic behaviors. FXS is the leading genetic cause of intellectual disability, affecting millions of children worldwide, however, there is currently no cure. FXS is caused by the absence of the Fragile X Mental Retardation Protein (FMRP). This FMRP deficiency activates the integrated stress response (ISR), promoting the internalization of AMPA receptors, concomitant with deficits in dendritic spine maturation and turnover. These synaptic deficits likely underlie the cognitive deficits observed in FXS. New therapeutic strategies have immense potential for the improvement of FXS patient quality of life, however there are currently no therapies targetting the ISR. The overall objective of this proposal is to determine the efficacy of ISR modulation by the novel drug ISRIB (ISR inhibitor) in normalizing the synaptic and cognitive deficits observed in FXS. Our central hypothesis is that blocking the ISR with ISRIB will stabilize spine maturation and turnover, alleviating the behavioral and cognitive deficits observed in FXS. Utilizing an Fmr1 knockout (KO) mouse model of FXS, we will address this hypothesis in the following specific aims: 1) Determine the effect of ISRIB treatment on synaptic phenotypes in Fmr1 KO mice and 2) Determine the effect of ISRIB treatment on cognitive and social deficits in Fmr1 KO mice. We will address these aims using a combination of molecular, imaging, and behavioral techniques. We will determine the effect of ISRIB treatment on spine maturation by measuring the abundance of post-synaptic membrane-bound AMPA receptors and spine dynamics by measuring the rate of formation and elimination. The effect of ISRIB on behavioral phenotyes will be assayed by a battery of social and cognitive tests. The outcomes of this research will define the role of the ISR in the etiology of FXS and has the potential to provide a foundation for the development of new strategies for therapeutic intervention in FXS. I have developed a detailed, tailored development plan for my training during this award period including technical, scientific, and professional training activities. I will build on my strong foundation in molecular biology as well as gain technical training in array tomography, two-photon microscopy, and mouse behavioral analysis. For scientific training, I will enroll in both formal courses as well as participate in seminars at Stanford. Professionally, I will enhance my career development through workshops, conference participation, and grant and manuscript writing programs. The training environment in Dr. Mourrain’s lab and at Stanford is exceptional. In addition to my research activities, in which I will gain new technical and scientific expertise, I will participate in a variety of development programs offered at Stanford including workshops in building a successful path to an independent academic career. Dr. Mourrain is committed to my comprehensive training and together we have developed a plan that will enable me to gain increasing independence throughout the course of my training.