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NCIRE-The Veterans Health Research Institute is the leading private nonprofit institute devoted to Veterans health research in the United States. Our mission is to advance Veterans health through research.

We support the work of some of the nation's foremost physicians and scientists at the San Francisco Veterans Affairs Medical Center, the premier biomedical research facility in the VA system. All have faculty appointments at the University of California, San Francisco, which has its own proud traditions of research and patient care. We also partner with the U.S. Department of Defense to support health research on behalf of our men and women in the Armed Forces.

Those who have served in uniform have given their best for their country. In return, we believe that they deserve nothing less than the best health care research we can provide.

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Raymond A. Swanson, MD

Staff Physician, Chief of Neurology and Rehabilitation Service, SFVAMC
Professor and Vice Chair of Neurology, UCSF


PARP-1, Inflammation, and Brain Cell Death

Cell death in the CNS has several unique features stemming from the special characteristics of excitable cells.  I have a longstanding interest in excitotoxic and oxidative neuronal death, and in particular, the role of bioenergetics in these processes.  A current focus of my work is the ubiquitous nuclear enzyme, poly(ADP-ribose polymerase-1 (PARP-1).   PARP-1 is normally functions in DNA repair, but which also mediates bioenergetic failure during excitotoxic and oxidative cell death.  PARP activation is also an important mediator of microglial activation by virtue of its interaction with the transcription factor NF-kB.  A major aim of my research program is to elucidate the bioenergetic events between activation of PARP and cell death under disease conditions in brain.  A related question concerns the cellular origin of oxidative stress that activates PARP-1.  Oxidant production in neurons is widely attributed to the mitochondria, but superoxide is produced by NADPH oxidase in response to neuronal NMDA receptor activation.  This superoxide signal normally contributes to synaptic remodeling, but it can also produce oxidative stress and cell death. We are now working to identify key regulatory steps in the signaling pathways linking NMDA receptors to NADPH oxidase function. Importantly, NADPH oxidase requires glucose to regenerate NADPH substrate, thus forming another intriguing link to cell bioenergetics.  A second source of oxidative stress is impaired oxidant scavenging.  We have identified the “glutamate” transporter EAAT3 as the major route of neuronal cysteine uptake.  Mice that lack EAAT3 have reduced glutathione levels in neurons and undergo age-dependent neurodegeneration and cognitive impairment. The dopaminergic neurons of the substantia nigra are particularly affected.  These studies are germane to Parkinson’s disease, ischemia, and other conditions in which oxidative stress contributes to neuronal demise.

To see Dr. Swanson on Pub Med, click here.