Fragile X syndrome (FXS), the most common heritable form of intellectual disability and most common single-gene form of autism, is caused by partial or complete silencing of the fragile X (FMR1) gene upon expansion of a CGG-repeat element within the gene, leading to loss of the FMR1 protein (FMRP). The protein is important for brain development, and its loss is accompanied by both intellectual and behavioral disability. The purpose of the research is to identify therapeutic agents that increase FMRP from residual FMR1 messenger (m)RNA, thereby reversing the effects of decreased gene activity. The scope of our project has been to block repressive interactions between microRNAs and the FMR1 mRNA, thereby increasing protein levels; and to screen a large library (20,000 compounds) of small molecules for those with the ability to increase FMRP levels. Major findings/accomplishments include: (i) upregulation of FMRP expression by 1.7-fold through the miRNA blocking agents, (ii) utilization of a fast FMRP screen to test 5,000 small molecules for their ability to upregulate FMRP; and (iii) identification of impairments in calcium dynamics, which can be used as a biomarker for treatment approaches. The significance of this work is underscored by the fact that nearly two-thousand children of service personnel are likely to have fragile X syndrome, with a much larger number (7,500) of active military personnel being carriers of an expanded (premutation) form of the FMR1 gene.