Degeneration and regeneration in the peripheral nervous system involve a complex interaction between neurons, schwann cells, and infiltrating macrophages, as well as other cells. A full understanding of neurotoxic insults to peripheral nervous system requires an elucidation of these cellular interactions and the biochemical mechanisms involved in degeneration and regeneration. The long term objective of this project is to compare toxic neuropathies with Wallerian degeneration in order to distinguish cellular and biochemical changes that are generic responses to injury from those responses specific to a particular toxicant. The immediate specific aims include exploring the mechanisms by which lipoproteins (esp. apolipoproteins E and A-1) function in the transport and reutilization of degenerating myelin cholesterol, to elucidate the nature and role of the cells involved in this process (especially macrophages), and to examine how these phenomena may differ in particular neuropathies. The role of lipoproteins in the transport and metabolism of cholesterol liberated from degenerating myelin will be studied by examining cellular sites of production of apolipoprotein E, LDL receptor and HMG-CoA reductase by immunohistochemistry and in situ hybridization, by characterizing the lipoproteins involved, and by examining the fate of myelin cholesterol biochemically as well as by autoradiography. We shall also examine these neuropathies in transgenic apolipoprotein-minus mice. In addition to the in vivo models, the use of tissue culture models of degenerating and regenerating nerve will permit definition of the individual roles of the various components of this process by allowing manipulation of the chemical and cellular milieu in which degeneration is taking place. The roles of macrophages in the degeneration and regeneration processes will be examined by destroying them pharmacologically and studying nerve degeneration and regeneration in their absence. Finally, models of partial degeneration of nerve will be examined for cellular and biochemical alterations in the surviving nerve fibers.
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