Marian Kies Memorial Award for 2000
Dr. Sarah Robb
Dr.
Sarah Robb
Dr.
Sarah Robb
Dr. Sara Robb was the recipient of the 2000 Marian Kies Award. During her graduate work she identified the mechanisms of peroxide-induced oxidative stress in astrocytes. Astrocytes are a specific glial cell type in the brain charged with providing protection and trophic support to neurons and oligodendrocytes. Thus, loss of astrocyte function through oxidative stress could contribute to neurodegeneration. She used enriched mouse astrocyte cultures and tertiary-butyl hydroperoxide (tbOOH) to study astrocyte oxidative stress. Addition of tbOOH caused an increase in cytosolic calcium, loss of mitochondrial membrane potential and increased generation of superoxide. Generation of superoxide occurred in the mitochondria, as demonstrated by confocal colocalization of dihydroethidium oxidation and mito-tracker green. Additionally, mitochondrial swelling and disruption of cristea were observed by electron microscopy in tbOOH treated astrocytes. All of the aforementioned events occurred prior to loss of astrocyte viability, suggesting mitochondrial changes mediate astrocytic oxidative cell death. Because astrocytes contain both inducible (iNOS) and constitutive (cNOS) forms of nitric oxide synthase, NO may play an important role in astrocyte oxidative stress. When astrocytes were activated with LPS/INFg to produce iNOS, prior to the addition of tbOOH, cell death was delayed. This protection was reversible by L-NAME and the NO scavenger carboxy-PTIO. In addition, astrocyte activation with LPS/INFy decreased mitochondrial superoxide generation, preserved mitochondrial membrane potential, and decreased mitochondrial swelling in response to t-bOOH. In astrocytes oxidatively stressed with dopamine, endogenously produced NO also decreased measurable superoxide at mitochondria and decreased mitochondrial swelling. Dr. Robb’s studies demonstrated that astrocytes are vulnerable to oxidative stress and that their mitochondria are the target of this stress. She further identified factors that may afford protection to the astrocytes and their mitochondria. The results of her study are significant for understanding neurodegenerative disorders associated with oxidative stress and suggest that therapeutics under development should consider astrocytes as a target. Dr. Robb was a PhD student with Dr. James R. Connor at the Penn State College of Medicine.