De novo gene expression induced by endoplasmic reticulum (ER) stress plays a decisive role in determining whether neurons live or die following global cerebral ischemia. However, the molecular mechanisms regulating the balance between protective and damaging responses originating from the ER remain unsettled. We discovered that the ER-stress factor CHOP-10, previously linked to differentiation and apoptosis, induces ischemic tolerance in cortical neurons and is activated by the potent neuroprotective brain derived neurotrophic factor (BDNF). Importantly, we also found that loss of CHOP-10 expression alters neuritic responses to ischemia in the adult hippocampus. These results suggest that CHOP-10 plays a more complex role in the neuronal response to ischemic injury that previously recognized. In this proposal we test the hypothesis that CHOP functions as an integrator of both adaptive and pathological responses. Preliminary studies reveal that post-translational modifications induced by PKC and related kinase pathways have marked effects on the stability, localization and toxicity of CHOP-10. Using in vitro culture models and the 3-vessel occlusion model of transient global ischemia, we will define the mechanism(s) and role of BDNF-CHOP coupling. Together, these experiments seek to broaden our understanding regarding the role of CHOP-10 and ER stress responses in ischemic brain injury, and identify the molecular basis for ER-stress dependent transcriptional switching. Since CHOP itself is not a typical drug target, our focus on CHOP-kinase pathways may have important translational implications. The identification of suitable targets in this network could serve as the basis for therapies designed to inhibit delayed neuronal loss after ischemic brain injury.
In the United States an estimated 400,000 patients will suffer cardiac arrest each year, and in greater than 80% of cases a poor neurological outcome is expected;new treatment strategies are desperately needed. The current proposal focuses on a recently identified protective pathway in neurons involving the neurotrophic factor BDNF and the endoplasmic reticulum stress response factor CHOP-10. Progress in this area will enable the identification of drugs that can be used to protect the brain after cardiac arrest.