The projects in this proposal address fundamental questions in the normal development and maintenance of the peripheral nervous system, the pathogenesis of peripheral nerve diseases, and their mechanisms of repair. Project 1 is designed to determine the role of the axonal cytoskeleton and axonal transport in the regulation of axonal caliber both in normal development and in pathologic states. Integrated studies will explored the influences of axonal caliber on the myelin sheath. The organization of the Schwann cell cytoskeleton will be examined both in vivo and in vitro. Project 2 will used biochemical approaches and in situ hybridization with recently developed cDNA probes to examine the regulation of myelin formation in normal nerves and during development, remyelination, regeneration, and rapid alterations in axonal caliber. These approaches will be applied to human nerve biopsies as well as experimental models. Project 3 will examine mechanisms of myelin formation. Immunocytochemical studies will define the timing and the appearance of myelin proteins at specific stages of axon-Schwann well interactions. Electron microscopie autoradiographic studies will explore the mode of delivery and insertion of proteins and glycoproteins into the myelin sheath, and how this insertion might be altered during remyelination or circumferential expansion of myelin lamellae. Project 4 will examine aspects of Schwann cell proliferation, migration, adhesion, and differentiation including determination of the source of new Schwann cells following paranodaldenyelination, the extent to which Schwnn cells migrate to regions of demyelination the biochemical effects of axolemma-enriched preparations on Schwann cells in vitro and in vivo. Project 5 is designed to identify nerve antigens toward which immune responses are directed in human inflammatory neuropathies; in particular, the hypothesis that glycolipid antigens are pathogenetically important will be tested. The cellular responses in nerve biopsies and spinal fluid will be examined systematically in immune mediated and heritable neuropathies. In these studies the approaches to be used are highly integrated with respect to the personnel, methods, and models. The results will provide new insights into normal cellular function in the peripheral nervous system, as well as the pathogenesis of peripheral nerve disorders.
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