Lisa Ann Gabel, PhD - US grants

DESCRIPTION (provided by applicant): The overall goal of the proposed experiments is to characterize the mechanisms that regulate the activity-dependent translation and degradation of Fragile X mental retardation protein (FMRP). Fragile X syndrome is the most common form of inherited mental retardation. This disease is caused by transcriptional silencing of the FMR1 gene and thus loss of expression of FMRP. Recent work indicates that FMRP is an RNA-binding protein involved in the regulation of protein synthesis-dependent synaptic plasticity. Furthermore, FMRP itself may be subject to translational regulation by synaptic activation. Preliminary studies from our laboratory indicate that: 1) visual experience induces transient expression of FMRP in the visual cortex of dark reared/light exposed rats; 2) cytoplasmic polyadenylation element and the CPE binding protein may play a role in the translational activation of FMR1 mRNA following visual experience; 3) the ubiquitin system may be involved in the rapid disappearance of FMRP. The translation and subsequent rapid degradation of FMRP could be important factors in regulating protein synthesis-dependent synaptic modification. In the proposed experiments we will further elucidate the cellular and molecular mechanisms that regulate FMRP expression during synaptic plasticity.

We seek to examine the connection among genetic, cognitive and behavioral aspects of reading disorder (RD) toward the goal of early identification and intervention. RD is a global concern affecting 5-17% of the world?s population, with far-reaching social and economic consequences. Several cognitive and perceptual changes appear to associate with RD, however it is unclear how cognitive, behavioral, and genetic measures correlate with RD. The goal of the proposed research is to use a multidisciplinary approach to examine the link between specific genetic variants, impaired visuo-spatial ability, and measures of reading performance in pre-readers (5-6 years of age) and children of reading age (8-13 years old). We will reach this goal by using a virtual maze environment designed by Lafayette College students which enables us to translate visuo-spatial performance on the Hebb-Williams maze across species, between mice and human adults and children. Accurate rendering of virtual environments allows for cross-species comparisons between animal models of RD and humans with the disorder, in order to gain a better understanding of the biological basis of reading impairment. In this study, we will confirm our recent findings that children (8-13 years old) with RD are impaired on the virtual task, and examine genetic risk variants for RD. In addition, we will perform similar analyses in pre- readers, and confirm their reading status with more reliable measures of reading at age ?8 years. We will accomplish these goals through the following specific aims: 1) Determine whether altered visuo-spatial abilities on the virtual Hebb-Williams maze in children with RD are associated with candidate dyslexia susceptibility gene (CDSG) genetic risk variants, 2) Determine whether altered visuo-spatial abilities on the virtual Hebb-Williams maze in pre-readers correlate with CDSG genetic risk variants; 3) Determine best predictor of future reading ability following longitudinal study of reading and virtual maze performance. These data will allow us to examine cognitive, behavioral and genetic data in order to better understand which measurements are the best indicators of future reading ability. These data will provide powerful information toward our long term goal for early detection of children at risk for reading disorder. Early detection and intervention will help to close the gap between typically developing and reading disabled children in acquiring reading skills. This work directly aligns with the mission of NICHD to ensure ?that all children have the chance to achieve their full potential for healthy and productive lives.? The complete explanation of a complex neurodevelopmental disorder requires an understanding across multiple levels, including, but not limited to, cognition, behavior, and genetics. These studies are essential in order to understand the link between CDSG expression in human cell lines and mice, and cognitive processing deficits reported in individuals with dyslexia. In addition, we will determine whether the virtual Hebb-Williams maze is a suitable low cost, time efficient, easy-to-use tool for early detection of specific reading impairment.