Defining Neurotherapeutic Targets in Hypoxia-Induced CHOP-10 Signaling Networks

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Stroke places a significant burden on our patients and their families, and has a major economic impact on society. While advances in the areas of revascularization have improved our ability to treat this devastating disorder, the development of neuroprotective drugs targeting the delayed neuron loss has not kept a pace. Protective strategies that target the acute phase of necrotic cell loss after stroke have failed in clinical trials. Our belief, which is supported by evidence from imaging data in humans, is that these Interventions fail to address the wave of neuronal cell death that matures during the hours to days after the inciting stimulus. We seek to identify new molecular targets and therapies that can alter transcriptional responses in endangered brain tissue, which without intervention Is destined to die. We envision that therapies based on our discoveries would complement Intravenous or Intra-arterial thrombolysis protocols after focal stroke, and In patients who have sustained global anoxic brain injury after cardiac arrest. Hypoxia is a key physiologic component of stroke, and our studies indicate that the endoplasmic reticulum (ER) plays a major role in stimulating de novo adaptive and pathological gene expression in neurons. We have identified a cluster of bZIP transcription factors that are activated in other paradigms involving ER stress. One factor of particular Interest is the protein Chop-10 (ddit3/gadd153). While most published studies indicate Chop serves a pathological role, our data suggests Chop promotes adaptive signaling In the face of hypoxic challenge. We also find that Chop is subject to post-translational modification (PTM), and that Chop may tie required for BDNF induced neuroprotection. In this updated ROO proposal we focus on understanding the factors governing Chop's ability to either protect or trigger cell death programs in neurons. Discoveries made during the K99 phase have led us to define the upstream signals linking BDNF mediated protection with Chop activation. These studies buikj upon progress made during the K99 phase and use a variety of molecular genetic tools to study Chop-10 biology in stroke-relevant experimental paradigms. We anticipate that our results will aid in the identification of novel and tractable therapeutics for stroke.