We postulate a novel cell biological mechanism termed axonuclear communication which functions to link glial cell cytoplasm with neuronal cell bodies via transfer of protein-synthesizing units and mRNA from glia to axon, local protein synthesis of critic al components in the axon, and importinmediated axonal retrograde transport of the signaling complexes thus created. Our central aim is to understand and control axonuclear communication to eventually allow support and therapeutic intervention for diseas ed and damaged nerve cells via engineering critical steps along the glia-axonneuronal cell body route. We will elucidate the mechanisms involved in glia to axon transfer of ribosomes and importin transcripts and their local translation, and in importin-ta rgeted retrograde trafficking along axons to the neuronal cell body and nucleus. In addition we will examine the involvement of axonuclear communication in motor neuron disease, in viral invasion of the nervous system, and in neuropathic pain mechanisms. The potential impact of understanding and controlling axonuclear communication is significant both in terms of basic understanding of how the nervous system works, and in terms of potential downstream applications in a range of clinical settings. The lat ter include the very exciting possibility of utilizing the system for targeting therapeutic support or gene therapy to the brain. One may conceive using axonuclear communication mechanisms to target desired molecules from the periphery to specific locati ons in the CNS, or to improve delivery of a neuroprotective gene to defined neuronal populations. The extreme difficulty of transfecting neurons with exogenous genes is well known, and therein lies perhaps the most promising impact of the project, if we can develop knowledge that will allow future introduction of gene therapy to neurons by transfecting glia with vectors engineered to enter neurons via the axonuclear communication route.
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