Gag-like Proteins in exosome-mediated Neural Development and Fetal Alcohol Spectrum Disorders

项目总结

Project Summary Prenatal alcohol exposure (PAE) can result in a collection of brain-based disabilities termed Fetal Alcohol Spectrum Disorders (FASD). FASDs are estimated to affect ~1-5% of school-aged children in the US. While sociocultural factors make PAE difficult to prevent, FASD may be prevented by early interventions. The proposed studies, aimed at identifying novel, alcohol-sensitive brain growth control mechanisms mediated by a family of Gag-Like Proteins (GLPs), may uncover new ways to minimize effects of PAE. GLPs are genomic remnants of ancient retroviral infections that have since been adapted for utilization in the host organism. Some have evolved to control transcriptional regulatory networks in embryonic stem cells, whereas others like Arc facilitate plasticity in differentiated neurons, and have been hypothesized to mediate some cognitive deficits observed in neurodevelopmental disorders like Angelman’s syndrome. Arc has also recently been identified as a capsid forming protein capable of transporting its own mRNA in exosomes between neural cells, reminiscent of its Gag origin. Other GLPs may also retain functional aspects of Gag, such as the ability to interact with mRNAs and to self-target for membrane bound export. These data raise the exciting possibility that GLPs may facilitate intercellular transfer of RNAs and therefore serve as a means for programming the development and maturation of neural stem cell ensembles. Preliminary data indicate that expression of two GLPs (PEG10 and PNMA2) are selectively induced in fetal neural stem cells, following alcohol exposure. The overarching hypotheses are that these GLPs, through both intracellular mechanisms and exosome-mediated intercellular communication, control neural stem cell renewal and facilitate neurogenesis, and that perturbations in GLP expression due to alcohol exposure will result in loss of stem cell renewal and diminished neurogenesis. The immediate goal will be to identify RNA and protein partners of GLPs PEG10 and PNMA2 which mediate ethanol-effects on neural differentiation and development. Aim 1: Determine the intracellular role of Gag-like proteins PEG10 and PNMA2 in the basal and ethanol influenced differentiation of neural stem cells and neural development. Aim 2: Determine the extracellular role of PEG10 and other Gag-like proteins present in exosomes in intercellular communication and coordination of neural development under basal and ethanol conditions. Aim 3: Determine the in vivo interaction between Gag-like proteins and PAE on fetal neural development. These studies are expected to uncover novel GLP mediators of differentiation that may be manipulated in exosomes to control self-renewal and maturation of neural stem cell ensembles and to minimize effects of PAE on early neural development. This training plan’s focus on disrupting the connection between PAE and FASD integrates well with a career goal to become a pediatrician-scientist with a focus on developmental disabilities.