Uniformed Services University of the Health Sciences
4301 Jones Bridge Road
Bethesda, Maryland 20814
The long-term goal of my laboratory is to study the cellular and molecular mechanisms of glial and neuronal toxicity and the pathogenesis of neurodegenerative diseases.
Brain injury is often accompanied with inflammation. Nitric oxide and its reaction product with superoxide, peroxynitrite, are the major toxic species released from the reactive astrocytes and microglia. We are now particularly interested in elucidating the signaling pathways of peroxynitrite toxicity to oligodendrocytes (OLs) using primary cultures from rat and mice brain. Our previous work has suggested that activation of arachidonic acid metabolism plays an important role in the toxicity of peroxynitrite to premyelinating OLs (preOLs) and to mature OLs that produce myelin basic protein. However, distinct cell death pathways are involved in these two cell types. We are now investigating these cell death mechanisms using pharmacological, biochemical and molecular approaches in culture, and testing whether these signaling molecules are critical in the animal models of cerebral palsy and multiple sclerosis, the two major demyelinating diseases found in premature infants and young adults, respectively.
Another area of the research is to study the mechanisms of motor neuron injury in amyotrophic lateral sclerosis (ALS). Although motor neuron dysfunction and degeneration are hallmarks of ALS, recent evidence indicates the toxicity of the mutants of Cu/Zn superoxide dismutase (SOD1), which cause one form of familial ALS, is non-cell autonomous, suggesting that the interplay between neurons and other cell types might play an important role in the pathogenesis of ALS. We will use biochemical, molecular and proteomic approaches to uncover the specific cellular components that contribute to the toxic effects of astrocytes or microglia and the increased vulnerability of motor neurons to the toxic stimuli.