There is an abundant pool of glial progenitor cells (GPCs) dispersed throughout adult human brain tissue. This proposal seeks to define the niche for astrogliogenesis in the human white matter, with an emphasis on defining the molecular basis for reactive astrocytosis. Absent autocrine and paracrine influences, adult GPCs are not restricted to any given neural lineage. Rather, the environment regulates their differentiated fate, suggesting that an ischemic environment might specifically direct GPCs to astrocytic fate in reactive astrocytosis. On this basis, we investigated the gene expression patterns of adult human GPCs derived from normal brain tissue. We identified a set of parallel and interacting ligand-receptor interactions, as well as their cognate signaling pathways, that may to determine whether a given GPC remains undifferentiated, or instead develops into an astrocyte, oligodendrocyte, or neuron. We now propose to define those pathways involved in both normal and post-ischemic astrocytosis from adult human glial progenitors. By this means, we expect to identify genetic and pharmacological targets by which to suppress reactive astrocytosis following ischemic injury, while sustaining our ability to mobilize progenitors to desired lineages. To this end, we shall focus on several pathways that appear differentially expressed in isolated GPCs. These include receptor tyrosine phosphatase-p/^ (RTPZ), which may play a central role in modulating li-catenin trafficking, its chondroitin sulfate proteoglycan ligands, and two interacting receptor systems, the FGFR3 tyrosine kinase, and the BMP4-dependent serine/threonine kinases. Specifically, weask: 1. Does the inhibition of RTPZ signaling suppress astrocytosis in vitro? Is this effect mediated by impeding B-catenin translocation? Can RTPZ inhibition suppress glial scar formation in vivo? What are the functional effects of suppressing post-ischemic gliosis through RTPZ inhibition? 2. Can reactive astrocytosis and glial scar formation after stroke be prevented by inhibiting BMP4-signaled astrocyte induction? What BMP inhibitors are best for this purpose? 3. How does the RTPZ pathway interact with FGFR3 and BMP signaling to instruct astrocytic fate? 4. Does the expression of CSPGs by GPCs produce an environment biased to astrocytosis, through CSPG-dependent activation of RTPZ? Can astrocytosis be suppressed through CSPG inactivation? Can concurrent RTPZ suppression further attenuate gliosis? What are the functional consequences of these strategies, in particular after MCA occlusion? The implications of this work are profound, not only in regards to stroke and trauma, but more broadly with regards to diabetic and hypertensive encephalopathies, which share an hypoxia-triggered disruption of the normal niches for cell genesis in the brain. In each of these disorders, reactive astrocytosis culminates in the sclerotic pathology that typifies terminally non-regenerative brain and spinal cord. Our goal is too prevent this fate, and by so doing preserve the cellular plasticity and regenerative capabilities of the healthy CNS.
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