Development of a Small Molecule P2X7R Antagonist as a Treatment for Acute SCI
Final rept. 15 Sep 2010-14 Sep 2013
ROCHESTER UNIV NY
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We have identified the transcriptional events associated with spinal cord injury SCI in FACS-isolated spinal astrocytes and microglia, with a focus on P2X7R-dependent transcription. We did so by establishing fluorescence-activated cell sorting FACS protocols by which we extracted distinct populations of spinal astrocytes and glial progenitor cells from both injured spinal cords and their normal controls. We then microarrayed the expressed RNAs of contused spinal cords, as well as from matched uninjured controls, so as to establish the injury-associated, phenotype-specific patterns of gene expression by astrocytes as microglia. These data have allowed us to define the cell-type specific responses of astrocytes and microglia to SCI, as well as the injury-specific paracrine interactions between these phenotypes, and the potential role of P2X7R in those interactions. Using this information, we identified a number of targets for therapeutic intervention. Among these, we found that pleiotrophin, a negative regulator of the receptor tyrosine phosphatase-betazeta PTPRZ1 of glial progenitor cells GPCs, can relieve PTPRZ1s suppression of progenitor cell expansion, and potentiate oligodendrocyte production. In addition, our bioinformatics analysis has identified novel drug combinations with potential therapeutic value, over and above P2X7R inhibitors, that should provide ample opportunities for new, glial-targeted drug development in SCI.
- Genetic Engineering and Molecular Biology
- Anatomy and Physiology
- Medicine and Medical Research