Genetics Analysis of Neuronal Hypoxic Stress Resistance

Project Details


DESCRIPTION (provided by applicant): Traumatic brain injury (TBI) and ischemic stroke are leading causes of morbidity and disability, excitotoxically killing neurons via hypoxia. The underlying mechanism is thought to be a combination of glutamate receptor overactivation, deregulated calcium homeostasis, and mitochondrial dysfunction. Specifically, the hypoxia resulting from trauma or stroke results in membrane depolarization and hence the 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. Mitochondrial dynamics become altered, influencing the production of ATP, as well as the release of calcium and Reactive Oxygen Species (ROS) from neuronal mitochondria. Agents that directly interfere with glutamate 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. Many species, including mammals, have mechanisms by which they protect themselves from glutamate-mediated excitotoxicity, although these mechanisms are poorly understood. Indeed, the movement of glutamate 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? How else does hypoxia alter the cell biology of neurons? This proposal takes genetic, molecular, cell biological, and electrophysiological approaches in C. elegans to understand how hypoxia impacts neuron function. In Aim 1, it examines how hypoxia and components of the known hypoxia response pathway alter the membrane trafficking of receptors. In Aim 2, it characterizes how EGL-9, a prolyl hydroxylase that senses oxygen levels and responds to hypoxia, regulates LIN-10, a PTB/PDZ- domain protein (orthologous to the Mints) known to regulate glutamate receptor trafficking. In Aim 3, it examines how hypoxia and EGL-9 regulate mitochondrial dynamics through their regulation of DRP-1, a mediator of mitochondrial fission. In Aim 4, it examines the effects of this novel pathway on neuron survival in several neurodegenerative models. The proposed experiments advance the field in several ways. First, they identify a novel hypoxia response pathway. Second, they demonstrate how neurons use this novel pathway to protect themselves from hypoxia. Third, they show that regulated receptor trafficking and regulated mitochondrial dynamics are the underlying mechanism. Finally, they provide potential new therapeutic targets for minimizing brain damage following TBI and ischemic stroke. PUBLIC HEALTH RELEVANCE: Traumatic brain injury and stroke create conditions of hypoxia (low oxygen) in the brain, triggering the excessive release of the neurotransmitter glutamate. High levels of glutamate in turn kill neurons by over- activating their glutamate receptors. It is critical to understand how glutamate receptors are regulated in response to hypoxia in order to develop novel applications for the treatment and prevention of brain damage resulting after traumatic injury or stroke.
Effective start/end date4/15/127/31/21


  • National Institutes of Health: $275,050.00
  • National Institutes of Health: $282,976.00
  • National Institutes of Health: $322,396.00
  • National Institutes of Health: $322,360.00
  • National Institutes of Health: $305,796.00
  • National Institutes of Health: $370,048.00
  • National Institutes of Health: $49,217.00
  • National Institutes of Health: $356,128.00


  • Medicine(all)
  • Biochemistry, Genetics and Molecular Biology(all)

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