HEREGULIN ACTIVATION OF SCHWANN CELLS

描述（来自申请人摘要的逐字描述）： 该项目旨在阐明控制雪旺细胞的分子机制 分化本申请的目的是研究 heregulin生长因子激活信号受体的机制 雪旺氏细胞。调蛋白是雪旺细胞增殖的关键调节因子， 分化和生存。神经细胞是调蛋白的主要来源， 外周神经和与轴突膜相关的heregulins已经被 显示促进雪旺细胞增殖和存活。至少有12个调蛋白 已知通过可变剪接产生同种型。这些同种型 显示出相当大的结构可变性。调蛋白激活细胞内 通过与跨膜受体结合在雪旺细胞中的信号通路 激酶erbB2和erbB3。受体结合是由一个保守的结构域介导的， 大约50个氨基酸存在于所有调蛋白中。拟议 实验将检验这一假设， 调蛋白异构体改变它们与靶细胞，如 雪旺氏细胞。这部分是由于膜结合的差异 以及某些调蛋白同种型与细胞表面硫酸乙酰肝素的相互作用 分子。具体目标涉及以下问题： heregulin功能和雪旺细胞。不同的影响是什么 heregulin结构对受体结合、内化和激活的影响 雪旺氏细胞？与硫酸乙酰肝素蛋白聚糖的相互作用如何影响 heregulins的活性？这些研究将用大鼠Schwann进行 在组织培养中生长的细胞和重组调蛋白。诱变 调蛋白同种型将用于鉴定特定的结构域， 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理解和治疗 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