HEREGULIN ACTIVATION OF SCHWANN CELLS

施万细胞的调蛋白激活

• 批准号: 6540416
• 负责人: David J. Carey
• 金额: $ 23.33万
• 依托单位: GEISINGER CLINIC
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-07-06 至 2005-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6540416
• 关键词: Schwann cells; biological signal transduction; carbohydrate biosynthesis; cell differentiation; cell growth regulation; cell proliferation; complementary DNA; enzyme activity; gene deletion mutation; heparan sulfate; heregulin; mitogen activated protein kinase; neurons; newborn animals; phosphorylation; polymerase chain reaction; protein binding; protein degradation; protein isoforms; protein structure function; proteoglycan; receptor binding; site directed mutagenesis; spinal ganglion; tissue /cell culture

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

描述（逐字研究来自申请人的摘要）：此的远程目标 项目是为了阐明控制Schwann细胞的分子机制 分化。当前申请的目的是调查 这里调节蛋白生长因子激活信号受体的机制 Schwann细胞。这里策略是Schwann细胞增殖的关键调节剂， 分化和生存。神经细胞是这里基团的主要来源 周围神经和与轴突膜相关的这里的神经蛋白已经 证明可以促进雪旺细胞的增殖和存活。至少12个gulin 已知通过替代剪接产生同工型。这些同工型 表现出很大的结构可变性。这里策略可激活细胞内 通过与跨膜受体结合，雪旺细胞中的信号通路通路 激酶ERBB2和ERBB3。受体结合是由一个保守域介导的 所有这里的蛋白中存在的大约50个氨基酸。提议 实验将研究以下假设 gresegulin isoforrns改变了其与靶细胞相互作用的能力，例如 Schwann细胞。这部分结果是膜关联的差异 以及某些这里策略蛋白同工型与细胞表面硫酸乙酰肝素的相互作用 分子。具体目的解决了以下问题 这里调节蛋白功能和雪旺细胞。差异的影响是什么 这里策略蛋白结构在受体结合，内在化和激活上 Schwann细胞？与乙酰硫酸乙酰肝素蛋白聚糖的相互作用如何影响 这里基团蛋白的活性？这些研究将与大鼠Schwann一起进行 在组织培养和重组蛋白中生长的细胞。诱变 这里调节蛋白的同工型将用于识别特定的结构域 产生功能差异。这些研究得出的信息将 促进对外围人类疾病的理解和治疗 神经系统和再生