COBRE: NE CREIGHTON U: P2: NEUROGULINS IN MYELIN REPAIR IN CNS & PNS

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This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. No body of literature examines the role of neuregulins, members of the epidermal growth factor superfamily, and their signaling molecules (erb family members) in response to in vivo virus-induced pathology, although they are known to be upregulated following injury to the peripheral nervous system. The studies in this proposal will examine the processes involved in the repair of the central and peripheral nervous systems (CNS, PNS respectively) following virus-induced damage to the myelin of the spinal cord and sciatic nerves. Thus, this proposal represents a novel approach to studying these proteins, and success in any of the specific aims would significantly enhance our knowledge of the PNS and CNS. In this application, we will test the hypothesis that neuregulins protect the CNS and PNS from Theiler¿s virus-induced pathology by enhancing myelination processes via erbB signaling. The following specific aims will be addressed in this application: 1) Test the hypothesis that neuregulin is upregulated in the central and peripheral nervous systems following TMEV-mediated insult. 2) Develop in vitro and in vivo models to test the hypothesis that increased erb-B2 signaling enhances myelination in the CNS and PNS. This specific aim will utilize 3 approaches: first, we will develop organotypic cultures of spinal cords and sciatic nerves and alter neuregulins in vitro to determine the effects on demyelination; second, we will develop targeted erb-B2 conditional over-expressing mice, and finally, we will use a viral vector to deliver neuregulin in vivo to virus infected mice. Peripheral neuropathies in humans have been attributed to both genetic (e.g. Charcot-Marie-Tooth disease) and environmental (e.g., diabetes) causes. Two pathologies can be observed in this condition, axonopathy or myelinopathy. Each of the specific aims will provide us with insights into the processes involved in maintaining / repairing myelin in the peripheral and central nervous systems following infection. Our long-term goal is to explore the possibilities of intervening in the demyelinating processes and alleviating the complications associated with these diseas