ROLE OF NEUREGULIN ON AXON/GLIA INTERACTIONS IN DIABETES

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Neuropathy associated with diabetes is one of the most common forms of neuropathy in industrialized countries. The role of neurotrophic factors in the development and treatment of diabetic neuropathy has been a major focus of research. However, comparatively few studies have addressed the use of growth factors on Schwann cells as a possible route of treatment for diabetic neuropathy. Since Schwann cells are ciritical for nerve regeneration but particularly sensitive to the effects of hyperglycemia, they may regulate the development of diabetic neuropathy. Neuregulins are responsible for Schwann cell survival, proliferation and maturation. Therefore, mitogenic properties of neuregulins may be critical to the regenerative response. Our long-range goal is to understand how Schwann cells and neurons interact during the process of nerve degeneration and subsequent nerve regeneration under hyperglycemic conditions. The objective of this application is to determine the direct effects of neuregulin on Schwann and dorsal root ganglion cells under hyperglycemic conditions in vitro. The central hypothesis is that hyperglycemic conditions reduce the expression of neuregulins in Schwann cells and neurons and erbB receptors on Schwann cells. This has the potential to impair Schwann cell proliferation and promote Schwann cell apoptosis. The studies in this proposal address the following specific aims to test our central hypothesis and achieve the overall objectives of this proposal. All experiments will be conducted on dissociated Schwann cells and dorsal root ganglion neurons in culture to assess the direct effects of hyperglycemia on these cell types. Specific Aim number 1 is to characterize the effects of hyperglyc emia on neuregulin and erbB receptor expression on Schwann and dorsal root ganglia cells. Using immunocytochemical and immunoblot analyses, protein expression will be localized and quantified in the specific cell types. Specific Aim number 2 is to determine if exogenously applied neuregulin prevents hyperglycemia-induced apoptosis in Schwann cells and dorsal root ganglion neurons. The proposed research has important clinical implications. By understanding the effect of neuregulins on the diabetic peripheral nerve, we can formulate new therapies to inhibit or prevent the progression of diabetic neuropathy. Indeed, the neuroprotective properties of neuregulins have been described in nerve crush and cisplatin-induced neuropathy. Their clinical importance in diabetic neurpathy, however, has not yet been investigated.