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Transcription-based Therapies for Stroke

Phosphatase Regulation of HIF-1-dependent transcription


TTC stained brain sections from a mouse
that underwent 1 hour of MCA occlusion.
Areas of injured (white)
tissue with associated hemorrhage
can be observed in the cortex and basal ganglia.

De novo gene expression induced by the hypoxia inducible factor (HIF-1α 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-1α cleavage near the amino-terminal transactivation domain and triggers both BNIP3 expression and a host of related pro-apoptotic responses. In this project we test the hypothesis that MKP-1 and HIF-1α 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-1α post-translational modification
  2. The discrete modifications and factors required for HIF-1α cleavage
  3. The effects these changes have on neuron survival.

Together, these experiments focus on a novel, physiologically responsive signaling node that modulates HIF-1α’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.

Relevant Publications

Patent Activity

Methods of treatment and screening assays for hif-1alpha regulation (US 20120251629 A1)

Defining Neurotherapeutic Targets in Hypoxia-Induced ER Stress Signaling Networks


STRING analysis of protein-protein networks
between the key ERSR bZIP factors
CHOP-10 (ddit3), ATF4, ATF6 and C/EBPb.

Stroke is the third leading cause of death in the U.S. Hypoxia is central to the pathogenesis of this disorder, and is a potent stimulus for gene expression. Adaptive failure in the face of severe metabolic crisis triggers a transcriptionally-dependent form of delayed neuronal death affecting selectively vulnerable neuronal populations across the CNS. The bZIP family of transcription factors associated with the endoplasmic reticulum stress response function as intermediates in sensing oxygen stress and regulate the balance between adaptive to pathologic transcription. These studies investigate the causal relationship between severe hypoxic stress, the coordinated regulation of ER-dependent bZIP signaling, and resultant effects on neuron survival in models of global ischemia.

Relevant Publications

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