Project 5:
CNTF Promotes Neuronal Survival and Axonal Sprouting
Investigator: Dr. John Watt

Neurotrophic factors can prevent and reverse neuronal cell death associated with CNS disorders. Consequently, neurotrophic factors in general and ciliary neurotrophic factor (CNTF) in particular continues to be considered attractive therapeutic targets for the treatment of a variety of acute and chronic neurodegenerative conditions. However, despite the potential clinical importance of CNTF, little is known regarding its expression in adult brain and 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. In support of this hypothesis, we have demonstrated an endogenous glial source of CNTF in the supraoptic nucleus of the magnocellular neurosecretory system (MNS). Results of immunocytochemical and in situ hybridization analysis demonstrated that axotomy significantly increased CNTF expression in both the axotomized supraoptic nucleus and in the contralateral intact supraoptic nucleus from which axonal sprouting originates. Furthermore, we have shown activation of Signal Transducer and Activator of Transcription (STAT) proteins in response to both axotomy and following direct infusion of rat recombinant CNTF (rrCNTF) in the supraoptic nucleus in vivo. We will apply a novel systems biology approach to investigate the role of CNTF and specific signal transduction pathways in promoting post-injury neuro-restorative functions. The innovation of the proposed studies lies in our ability to induce an apoptotic response in identified magnocellular neurons through infundibular nerve crush injury, monitor the neuronal decline through external physiological measures, and then reverse that decline through direct intervention with exogenous rrCNTF. This model will also allow detailed analysis of the specific signaling pathways evoked as a result of both the injury and the CNTF treatment and the subsequent downstream induction of other growth factors and cytokines which support neuronal survival and process outgrowth in young v mature rats. Elucidating the mechanisms by which CNTF mediates neuronal survival either through direct actions on neurons or indirectly through glial activation will provide a significant advancement in our understanding of the mechanisms by which neurotrophin-mediated cellular activities are controlled throughout the CNS. Moreover, our findings will contribute to the knowledge base necessary for the development of intervention strategies for those conditions where CNTF or other growth factors may contribute to neuro-restorative functions.