Targeting phosphatase regulated cleavage of HIF-1-alpha in ischemic brain injury

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DESCRIPTION (provided by applicant): De novo gene expression induced by the hypoxia inducible factor (HIF-1a) plays a decisive role in determining whether neurons live or die after an ischemic insult. However, the molecular mechanisms regulating the balance between HIF's adaptive and pathological effects remain unsettled. We have discovered that the MAP kinase phosphatase MKP-1 stimulates HIF-1a cleavage near the amino-terminal transactivation domain and triggers both BNIP3 expression and a host of related pro-apoptotic responses. In this application we test the hypothesis that together, MKP-1 and HIF-1a function as a molecular switch during ischemia, promoting the expression of genes involved in autophagy and apoptotic signaling. We will use complimentary genetic approaches applied in culture and animal models of ischemic injury to investigate: 1) the mechanism by which MKP regulates HIF-1a post-translational modification, 2) the discrete modifications and factors required for HIF-1a cleavage, and 3) the effects these changes have on neuron survival. Together, these experiments focus on a novel, physiologically responsive signaling node that modulates HIF-1a's latent apoptotic potential. The identification of suitable targets in this network will enable the discovery of small molecules designed to either inhibit or augment transcription- dependent injury. Progress in this area will have broad implications for both ischemic and malignant brain disorders. PUBLIC HEALTH RELEVANCE: Brain injury after cardiac arrest is a common condition with devastating consequences ranging in severity from memory loss to coma and death. Ischemia-induced gene expression controlled by the oxygen- dependent transcription factor HIF-1a plays a decisive role in the survival of brain cells following ischemic insults. This application focuses on understanding the molecular basis for MKP-HIF-1a coupling, and seeks to find new treatment options for global ischemic brain injury based on our discoveries related to the interactions between these factors.