HEREGULIN ACTIVATION OF SCHWANN CELLS

描述(逐字摘自申请者摘要)：这是一个长期目标 该项目旨在阐明控制雪旺细胞的分子机制 差异化。当前应用程序的目标是调查 谷氨酸生长因子激活信号受体的机制 雪旺细胞。Heregulins是雪旺细胞增殖的关键调节因子， 分化和生存。神经细胞是HERG蛋白的主要来源 外周神经和与轴突膜相关的Heregulin已被 显示能促进雪旺细胞的增殖和存活。至少12个赫里格林 已知的异构体是通过选择性剪接产生的。这些异构体 表现出相当大的结构变异性。Heregulins激活细胞内 雪旺细胞与跨膜受体结合的信号转导途径 蛋白酪氨酸激酶erbB2和erbB3。受体结合是由一个保守的结构域 大约50个氨基酸，存在于所有的Heregulin中。建议数 实验将检验这样一种假设，即 HERG异构体改变了它们与靶细胞相互作用的能力，例如 雪旺细胞。这在一定程度上是由于膜结合的差异造成的 以及某些海藻糖素亚型与细胞表面硫酸乙酰肝素的相互作用 分子。具体目标是解决与以下问题相关的问题 谷蛋白功能与雪旺细胞。这些差异会带来什么影响？ HERG结构对受体结合、内化和激活的影响 雪旺细胞？与硫酸乙酰肝素蛋白多糖的相互作用如何影响 Heregulins的活性？这些研究将在大鼠施万德身上进行 在组织培养和重组Heregulin中生长的细胞。致突变性的研究 谷氨酸异构体将被用来鉴定特定的结构域， 产生功能差异。从这些研究中获得的信息将 促进对人类外周疾病的了解和治疗 神经系统与再生

DESCRIPTION(Verbatim from Applicant's Abstract): The long-range goal of this project is to elucidate the molecular mechanisms that control Schwann cell differentiation. The aim of the current application is to investigate the mechanisms by which heregulin growth factors activate signaling receptors on Schwann cells. Heregulins are key regulators of Schwann cell proliferation, differentiation, and survival. Nerve cells are a major source of heregulins in peripheral nerves, and heregulins associated with axonal membranes have been shown to promote Schwann cell proliferation and survival. At least 12 heregulin isoforms are known to be produced by alternative splicing. These isoforms exhibit considerable structural variability. Heregulins activate intracellular signaling pathways in Schwann cells by binding to the transmembrane receptor kinases erbB2 and erbB3. Receptor binding is mediated by a conserved domain of approximately 50 amino acids that is present in all heregulins. The proposed experiments will examine the hypothesis that structural differences among heregulin isoforrns alter their ability to interact with target cells, such as Schwann cells. This results, in part, from differences in membrane association and interaction of certain heregulin isoforms with cell surface heparan sulfate molecules. The specific aims address the following questions related to heregulin function and Schwann cells. What are the effects of differences in heregulin structure on receptor binding, internalization and activation of Schwann cells? How does interaction with heparan sulfate proteoglycans affect the activity of heregulins? These studies will be carried out with rat Schwann cells grown in tissue culture and recombinant heregulins. Mutagenesis of heregulin isoforms will be used to identify particular structural domains that produce functional differences. The information derived from these studies will facilitate the understanding and treatment of human diseases of the peripheral nervous system and regeneration