CNTF PROMOTES NEURONAL SURVIVAL AND AXONAL SPROUTING

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Neurotrophic factors in general and ciliary neurotrophic factor (CNTF) in particular continue to be considered attractive therapeutic agents for the treatment of a variety of acute and chronic neurodegenerative conditions including traumatic brain injury, Parkinson's and Huntington's disease and amytrophic lateral sclerosis. However, despite the potential clinical importance of CNTF, little is known regarding its expression in adult brain or the mechanisms of its actions in vivo. The long term goal of my laboratory is to gain a greater understanding of the mechanisms by which neurotrophins and related cytokines promote neuronal survival and process outgrowth in the damaged CNS. Our central hypothesis is that CNTF acts as both a neuronal survival factor and sprouting factor for magnocellular neurosecretory neurons in vivo through activation of specific signal transduction pathways. In support of this hypothesis, we have demonstrated that axotomy results in a significant increase in CNTF expression in both the axotomized supraoptic nucleus and in the contralateral sprouting supraoptic nucleus. Furthermore, we have preliminary data which shows activation of Signal Transducer and Activator of Transcription (STAT) proteins in response to axotomy and following direct infusion of rat recombinant CNTF (rrCNTF) in the supraoptic nucleus in vivo. In light of these observations, the objectives of the proposed studies are to: 1) Determine the specific signal transduction pathways involved in the magnocellular response to injury and to exogenous rrCNTF and their role in the promotion of neuronal survival and process outgrowth; 2) Define the cellular responses induced by chronically administered rrCNTF in vivo; and 3) Determine if stimulation of magnocellular neurons with exogenous rrCNTF will overcome the maturational decline in neuronal sprouting efficacy and determine if reduced CNTF or STAT activity contributes to this decline. Pursuit of these objectives will be accomplished in part using chronic infusion of growth factors, immunocytochemistry, Western blot analysis, quantitative RT-PCR, in situ hybridization, electrophoretic mobility shift assays and organotypic cultures. Eludicating the mechanisms by which CNTF mediates neuronal survival and axonal sprouting either through direct interactions on neurons or indirectly through glial activation will provide a significant advancement in our understanding of how neurotrophin-mediated neurorestorative activities are controlled throughout the CNS.