Genetic Analysis of Neuronal Hypoxic Stress Resistance

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Traumatic brain injury (TBI) and ischemic stroke are leading causes of morbidity and disability, excitotoxically killing neurons via a combination of hypoxia and oxidative stress, glutamate receptor overactivation, and deregulated calcium homeostasis. In particular, the hypoxia resulting from trauma or stroke results in membrane depolarization and hence release of the neurotransmitter glutamate from affected neurons. High levels of acute glutamate overactivate receptors on neighboring neurons, thereby resulting in calcium influx and excitotoxicity. Agents that directly interfere with receptor activation have had limited clinical applicability because of their dramatic effect on receptor physiological function. Thus, it is important to identify new therapeutic targets in order to mitigate excitotoxicity after TBI or stroke. The discovery that regulated trafficking of glutamate receptors can modify synaptic efficacy has changed the thinking about mechanisms by which receptors contribute to excitotoxicity after neuronal trauma. In particular, the movement of receptors into and out of synaptic membranes after post-trauma hypoxia in some cultured neuronal systems can modulate excitotoxicity. Do changes in glutamate receptor trafficking contribute to neuronal death in the intact animal, or are they part of a neuroprotective response to hypoxia? What factors regulate glutamate receptor trafficking in response to hypoxia? This proposal takes a genetic approach in C. elegans to understand how hypoxia impacts neuron cell biology. In Aim 1, it examines how hypoxia and the known hypoxia response pathway alters the membrane trafficking of receptors. In Aim 2, it characterizes how EGL-9, a PHD protein that senses oxygen levels, regulates LIN-10, a PTB/PDZ-domain protein known to regulate glutamate receptor trafficking, in response to hypoxia. The proposed experiments advance the field in several ways. First, they identify a novel hypoxia response pathway. Second, they demonstrate a new response pathway by which neurons protect themselves from hypoxia. Third, they show that regulated receptor trafficking is the underlying mechanism. Finally, they provide potential new therapeutic targets for minimizing brain damage following TBI and ischemic stroke.