Development of a Small Molecule P2X7R Antagonist as a Treatment for Acute SCI
Abstract
In year 2 of this project we focused on Aim 4, defining the transcriptional events associated with spinal cord injury (SCI) in isolated spinal astrocytes and microglia, concentrating on P2X7R activity-dependent transcription. In year 1, we established the injury-associated expression profiles of sorted adult spinal microglia, the analysis of which has validated the innate immune system as a critical initiator of spinal inflammatory injury, and which has provided us new targets for therapeutic intervention. In year 2 we then validated a set of new FACS protocols by which we isolated distinct populations of spinal astrocytes and glial progenitor cells, from both normal and injured spinal cords. Using these protocols, which are based on Glut1 and GFAP-dependent astrocytic sorting, and both A2B5 and CD140a-targeted isolation of spinal glial progenitors, we prepared RNAs from contused spinal cords, as well as from matched uninjured controls, for microarray analyses. With these genomic data, we are assessing phenotype-specific gene expression, as a dual function of injury and time after injury, so as to fully define the paracrine interactions between astroglia and microglia in response to SCI. Besides defining the effects of P2X7R activation and its blockade on phenotype-specific gene expression, this approach has allowed us to identify other targets for potential therapeutic intervention. In particular, we found that the cytokine pleiotrophin, which acts as a negative regulator of the receptor tyrosine phosphatase- / (PTPRZ1) of glial progenitor cells, can relieve the tonic suppression of progenitor cell expansion provided by PTPRZ1, and can thereby mobilize endogenous glial progenitor cells, thus contributing to reactive gliosis as well as to compensatory remyelination in SCI.
Document Details
- Document Type
- Technical Report
- Publication Date
- Oct 01, 2012
- Accession Number
- ADA569681
Entities
People
- Steven A. Goldman
Organizations
- University of Rochester