Rapid ischemic tolerance- Rapid events mediating protection
We have shown that protein degradation via the ubiquitin proteasome system regulates rapid ischemic tolerance (the one hour time window of protection following preconditioning). We have studied the rapid degradation of the pro-cell death protein Bim following preconditioning and the intracellular pathways regulating Bim ubiquitination and degradation. This molecular pathway is also currently being followed as a potential biomarker for breast cancer.
We also have focused on morphological events following preconditioning. We recently showed that protein ubiquitination was responsible for remodeling of the cell cytoskeleton, resulting in a change in the morphology of the neuronal dendrite. This change in morphology regulates protection against ischemia. We are now investigating further changes to the synapse and long-term consequences.
Genomics of preconditioning
A second time window of protection occurs 24-72 hours following preconditioning. This protection requires new protein synthesis and new gene expression. How these genes are regulated may identify novel therapeutic targets for the artificial induction of tolerance. In addition we are interested in whether the genomic signature from multiple preconditioning agents all evoke the same basic genomic pattern of gene regulation, or whether each has a unique signature. Understanding the underlying biology of the protective phenotype, to identify therapies for stroke and other acute neuropathological conditions, is the goal of this research.
Research Key Words: Ubiquitin, Bcl2, transcription factor, ischemia, stroke