Our lab is interested in CNS glial cell development, function, and pathology. We study the precursors of oligodendrocytes in the developing and adult CNS to understand how they repair myelin in the adult CNS and how they react to pathological conditions. We also study how astrocytes react to the presence of pathological changes and how pathological changes in astrocytes affect the other cells of the CNS. We continue to study Alexander disease, a degenerative brain disorder caused by mutations in GFAP, the gene encoding the major astrocyte intermediate filament protein. These mutations activate intracellular stress responses and change the astrocyte phenotype dramatically. They lead to astrocyte dysfunction that resembles a marked reactive astrocytosis and produces pathology in neurons, oligodendrocytes, and microglia. Indeed, the major genes upregulated in Alexander disease are immune-function genes, which activate microglia, and produce electrophysiological changes in neurons. As a pure astrocyte disease, Alexander disease gives us insights into mechanisms of pathological changes in astrocytes in epilepsy, strokes, infections, and neoplasms and helps us understand how astrocytes influence the other cells of the CNS. Large numbers of oligodendroyte progenitor cells (OPC) populate the adult CNS. What regulates their transition into mature and myelinating oligodendroytes (OL) is not well understood but is critical for developmental myelination, continued myelination in adulthood, and remyelination in demyelinating diseases. We have identified the CD82 tetraspanin molecule as a critical, positive, regulator of this transition. CD82 inhibits the HGF-c-met signaling pathway, the activation of which keeps OLs immature. In mature OLs downregulating CD82 activates c-met and causes the cells to revert to an immature stage. We are charactering the molecular changes that take place during this critical transition.  In collaboration with Guomei Tang and David Sulzer of Neurology, Guy McKhann of Neurosurgery, and Peter Sims of Systems Biology, we are studying the cellular and molecular changes in astrocytes and neurons that take place during the evolution of epilepsy and in the evolution of autistic-like behavior. Our collaborative group uses mouse models of Tuberous Sclerosis, a disease characterized by seizures and commonly by autism-spectrum disorders, in which cells have constitutively activated mTOR. RNASeq and ribosomal profiling and footprinting give us many genes that are transcriptionally regulated and also allow us to discover translationally-regulated gene expression. Our lab is interested in CNS glial cell development, function, and pathology. We study the precursors of oligodendrocytes in the developing and adult CNS to understand how they repair myelin in the adult CNS and how they react to pathological conditions. We also study how astrocytes react to the presence of pathological changes and how pathological changes in astrocytes affect the other cells of the CNS. We continue to study Alexander disease, a degenerative brain disorder caused by mutations in GFAP, the gene encoding the major astrocyte intermediate filament protein. These mutations activate intracellular stress responses and change the astrocyte phenotype dramatically. They lead to astrocyte dysfunction that resembles a marked reactive astrocytosis and produces pathology in neurons, oligodendrocytes, and microglia. Indeed, the major genes upregulated in Alexander disease are immune-function genes, which activate microglia, and produce electrophysiological changes in neurons. As a pure astrocyte disease, Alexander disease gives us insights into mechanisms of pathological changes in astrocytes in epilepsy, strokes, infections, and neoplasms and helps us understand how astrocytes influence the other cells of the CNS. Large numbers of oligodendroyte progenitor cells (OPC) populate the adult CNS. What regulates their transition into mature and myelinating oligodendroytes (OL) is not well understood but is critical for developmental myelination, continued myelination in adulthood, and remyelination in demyelinating diseases. We have identified the CD82 tetraspanin molecule as a critical, positive, regulator of this transition. CD82 inhibits the HGF-c-met signaling pathway, the activation of which keeps OLs immature. In mature OLs downregulating CD82 activates c-met and causes the cells to revert to an immature stage. We are charactering the molecular changes that take place during this critical transition.  In collaboration with Guomei Tang and David Sulzer of Neurology, Guy McKhann of Neurosurgery, and Peter Sims of Systems Biology, we are studying the cellular and molecular changes in astrocytes and neurons that take place during the evolution of epilepsy and in the evolution of autistic-like behavior. Our collaborative group uses mouse models of Tuberous Sclerosis, a disease characterized by seizures and commonly by autism-spectrum disorders, in which cells have constitutively activated mTOR. RNASeq and ribosomal profiling and footprinting give us many genes that are transcriptionally regulated and also allow us to discover translationally-regulated gene expression.

Pathology and Cell Biology