My research activities focus on the abnormalities of the developing nervous system that are caused by two neuroteratogenic agents: alcohol, (fetal alcohol syndrome) and lymphocytic choriomeningitis virus (congenital LCMV infection). Whereas these two research programs, particularly fetal alcohol syndrome, constitutes the core of my scholarly efforts, I have been interested in development of gene therapy for Alexander Disease, a disease of cerebral white matter that affects children, and neuroblastoma, a childhood cancer of the nervous system.
Fetal exposure to alcohol can severely and permanently damage the developing brain and can lead to fetal alcohol syndrome (FAS), which is the leading cause of mental retardation in theUnited States. Currently, there are no clinical remedies to prevent the neuronal losses induced by fetal alcohol exposure. Thus, an overarching goal of my research has been to identify agents, genes, and signaling pathways that can prevent alcohol-induced neuronal death in the developing brain.
Lymphocytic choriomeningitis virus (LCMV) infection during pregnancy severely injures the human fetal brain. children with congenital LCMV infection can present with a diverse set of neurological deficits, have a host of neuropathologic abnormalities and a wide range of neurologic outcomes. Our lab has developed a rat model for congenital LCMV infection that remarkably recapitulates the human condition. Our goal in this project is to determine the molecular mechanism by which the virus destroys the fetal brain. One of the novel and important finding of LCMV research is that the virus selectively infects astrocytes in the brain, in a region-specific manner, and uses astrocytes as the portal of entry. This finding formed the foundation of the next project; development of gene therapy for Alexander Disease. Alexander Disease (AlexD) is a disease of cerebral white matter. AlexD is caused by an autosomal dominant mutation of the gene for glial fibrillar acidic protein (GFAP), a protein expressed exclusively in brain astrocytes. Our goal in this project is to silence the mutant GFAP allele using RNAi technology. We plan to deliver the therapeutic vector to affected astrocytes using viral gene therapy vectors that are engineered to carry coat protein of LCMV, hence astrocyte specificity.