Mechanisms of Sympathetic Axon Pruning

交感神经轴突修剪机制

• 批准号: 7560352
• 负责人: Peter G Smith
• 金额: $ 32.15万
• 依托单位: UNIVERSITY OF KANSAS MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7560352
• 关键词: Actins; Address; Adult; Axon; Biological Models; Brain-Derived Neurotrophic Factor; Cell Death; Cell Membrane Permeability; Cells; Ceramides; Cytoskeleton; Diestrus; Disease; Dyes; Estrogens; Estrous Cycle; Event; Exclusion; Horns; In Vitro; Investigation; Ligands; Mediating; Membrane; Messenger RNA; Mitochondria; Molecular; Myometrial; NGFR Protein; Natural regeneration; Nature; Nerve; Nerve Growth Factor Receptors; Nervous system structure; Neural Pathways; Neurites; Pan Genus; Pathway interactions; Peripheral; Permeability; Phase; Physiological; Presynaptic Terminals; Protein phosphatase; Proteins; Rattus; Receptor Signaling; Rodent; Role; Screening procedure; Sensory Receptors; Signal Transduction; Signal Transduction Pathway; Smooth Muscle; Sphingomyelinase; Study models; Tissues; Up-Regulation; Uterus; Work; axonal degeneration; brain-derived neurotrophic factor precursor; cofilin; density; depolymerization; in vivo; insight; mitochondrial membrane; myometrium; nerve supply; neurotrimin; neurotrophic factor; novel

DESCRIPTION (provided by applicant): Remodeling of mature neural pathways involves both axonal outgrowth to establish new connections and axonal degeneration whereby terminations are eliminated. Mechanisms by which axon terminations are eliminated, or pruned, in the absence of cell death are poorly understood. Peripheral sympathetic innervation presents an especially tractable model for studying axon pruning under normal physiological and pathophysiological conditions. Sympathetic axon density in the virgin rodent uterus fluctuates rapidly during the estrous cycle, with terminal axons degenerating when estrogen levels rise and regenerating when they decline. We have shown that estrogen elevates uterine brain derived neurotrophic factor, and hypothesize that this contributes to sympathetic axon degeneration. We hypothesize that brain derived neurotrophic factor activates the p75 neurotrophin receptor, which stimulates intra-axonal ceramide formation. This promotes terminal axon degeneration through abnormal increases in membrane permeability and actin depolymerization. The present study investigates mechanisms whereby targets elicit selective terminal axon pruning. The first aim evaluates the hypothesis that p75NTR activation is responsible for inducing sympathetic axon degeneration under physiological conditions. In aim 2, we explore the hypothesis that p75NTR activation produces axon degeneration by increasing permeability of axonal membranes, and by promoting destabilization of the actin cytoskeleton. In aim 3, we investigate the nature of ligands produced by the target that incur axon degeneration. Specifically, the roles of BDNF, pro-NGF and neurotrimin will be assessed. These studies use tractable in vivo and in vitro approaches to explore relationships among target- derived ligands, neural receptors, and signal transduction pathways, and will provide novel information on how selective terminal axon degeneration is accomplished under physiological and pathophysiological conditions. Findings will be pertinent to understanding both organizing principles related to normal nervous system plasticity, and to disturbances in innervation in certain disease states.

描述（由申请人提供）：成熟神经途径的重塑涉及轴突生长，以建立新的连接和轴突变性，从而消除了终止。在没有细胞死亡的情况下消除或修剪轴突终止的机制知之甚少。外围交感神经神经神经神经介绍了一个特别易于处理的模型，用于在正常的生理和病理生理条件下研究轴突修剪。在发情周期中，处女啮齿动物子宫中的交感神经轴突密度迅速波动，当雌激素水平下降时，末端轴突在下降时退化。我们已经表明，雌激素会提高子宫脑衍生的神经营养因子，并假设这有助于交感神经轴突变性。我们假设脑衍生的神经营养因子激活p75神经营养蛋白受体，从而刺激轴内神经酰胺的形成。这通过膜渗透性和肌动蛋白去聚合的异常增加来促进末端轴突变性。本研究调查了靶向引起选择性末端轴突修剪的机制。第一个目的评估了p75NTR激活负责在生理条件下诱导交感神经变性的假设。在AIM 2中，我们探讨了以下假设：p75NTR激活通过增加轴突膜的渗透性以及促进肌动蛋白细胞骨架的不稳定而产生轴突变性。在AIM 3中，我们研究了靶标产生的轴突变性的配体的性质。具体而言，将评估BDNF，pro-NGF和神经特征的作用。这些研究使用可拖动的体内和体外方法来探索目标衍生的配体，神经受体和信号转导途径之间的关系，并将提供有关在生理和病理生理条件下如何实现选择性终末轴突变性的新信息。发现将与理解与正常神经系统可塑性相关的组织原理以及某些疾病状态的神经疾病的干扰。