ROLE OF NEUREGULIN ON AXON/GLIA INTERACTIONS IN DIABETES

与糖尿病相关的神经病变是工业化国家中最常见的神经病变形式之一。 神经营养因子在糖尿病神经病变的发生和治疗中的作用一直是研究的主要焦点。 然而，相对较少的研究已经解决了使用生长因子对雪旺细胞作为治疗糖尿病神经病变的可能途径。 由于雪旺细胞对神经再生至关重要，但对高血糖的影响特别敏感，因此它们可能调节糖尿病神经病变的发展。 神经调节蛋白负责雪旺细胞的存活、增殖和成熟。 因此，神经调节蛋白的促有丝分裂特性可能对再生反应至关重要。 我们的长期目标是了解许旺细胞和神经元在高血糖条件下神经变性和随后的神经再生过程中如何相互作用。本申请的目的是在体外高血糖条件下确定神经调节蛋白对雪旺氏细胞和背根神经节细胞的直接作用。 中心假设是高血糖条件降低了雪旺细胞和神经元中神经调节蛋白以及雪旺细胞上erbB受体的表达。 这有可能损害许旺细胞增殖并促进许旺细胞凋亡。 本提案中的研究涉及以下具体目标，以检验我们的中心假设并实现本提案的总体目标。 所有实验将在培养物中的分离的雪旺细胞和背根神经节神经元上进行，以评估高血糖症对这些细胞类型的直接影响。具体目标1是表征高血糖对雪旺氏神经节细胞和背根神经节细胞上的神经调节蛋白和erbB受体表达的影响。 使用免疫细胞化学和免疫印迹分析，将在特定细胞类型中定位和定量蛋白质表达。 具体目标2是确定是否外源性应用neuregulin防止高血糖诱导的雪旺细胞和背根神经节神经元凋亡。 这项研究具有重要的临床意义。 通过了解神经调节蛋白对糖尿病周围神经的影响，我们可以制定新的治疗方法来抑制或预防糖尿病神经病变的进展。事实上，神经调节蛋白的神经保护特性已经在神经挤压和顺铂诱导的神经病变中描述。 然而，它们在糖尿病神经病变中的临床重要性尚未被研究。

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.