CRCNS: Activity-dependent growth cone guidance

CRCNS：活动依赖性生长锥指导

• 批准号: 8287590
• 负责人: KYONSOO HONG
• 金额: $ 36.34万
• 依托单位: NEW YORK UNIVERSITY SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8287590
• 关键词: Accounting; Behavior; Biological; Biological Assay; Cell membrane; Computer Analysis; Computer Simulation; Cyclic Nucleotides; Data; Dependency; Detection; Development; Embryo; Endoplasmic Reticulum; Environment; Event; Goals; Growth Cones; In Vitro; Instruction; Interneurons; Intracellular Second Messenger; Ion Channel; Ligands; Measures; Membrane Potentials; Methods; Modeling; Molecular; Monitor; Natural regeneration; Nervous system structure; Neurites; Neurons; Neurotransmitter Receptor; Neurotransmitters; Principal Investigator; Property; Proteins; Reporting; Scientist; Second Messenger Systems; Semaphorin-3A; Signal Pathway; Signal Transduction; Simulate; Site; Spinal; Staging; Study models; Synapses; Testing; Whole-Cell Recordings; Xenopus; base; biological systems; environmental chemical; extracellular; human NTN1 protein; in vivo; injured; migration; nervous system development; netrin-1; neural circuit; neurotransmitter release; overexpression; prevent; programs; receptor; research study; response; spatiotemporal; therapy development; trafficking; voltage

Program Director/Principal Investigator (Last, First, Middle): HONG, KYONSOO PROJECT SUMMARY (See instructions): Navigation of growth cones to their targets is essential for the establishment of neural circuits during nervous system development. Growth cones, at the tips of growing neurites, navigate through a variety ofextracellular environments in which they must sense, integrate and respond to a myriad of signals. This project seeks to investigate the molecular mechanisms of integration of the multi-signaling pathways required for growth cone guidance during normal nervous system development. The complexity of the interactions of these multi-signaling pathways during growth cone guidance, such as coincident detection and cross-talk signaling, as well as their spatiotemporal changes during development, prevents their elucidation by biological methods alone. The goal of this project is to bring together biologists and computational scientists to determine the mechanisms by which neuronal activities evoked by multiple neurotransmitter-guidance signals are transduced before synaptic contacts are established, using well established experimental methods and advanced computational analyses. We aim to experimentally investigate the developmental changes in intrinsic growth cone properties that determine growth cone responses to external signals, i.e.,ion channels and neurotransmitter signals, and to encode them in a computational model that can simulate the normal growth cone behavior that occurs in response to external guidance signals during nervous system development in vivo. We will determine the effects of developmental stage-dependent changes in neurotransmitter and guidance signals on growth cone turning in vitro, and subsequently test their dependencies both in vitro and in vivo, and develop computational, multi-signal integration and chemo-sensing growth cone models. Multi-signal integration models will be used to simulate biological responses of growth cones, to predict the most biologically efficient bi-directional guidance signaling mechanisms and to predict whether there is sufficient data to allow a faithful representation of growth cone multi-signal integration to fully describe normal growth cone migration as it occurs in vivo. Chemo-sensing models will be used to decode the external environmental chemical gradients that growth cones encounter during their guidance in vivo, and predict the essential environmental parameters required for growth cone behavior to allow their confirmation by direct experimentation. RELEVANCE (See instructions): Together, our experimental studies and computational modeling, will broadly impact our understanding of the multi-signaling mechanisms required to establish functional neural circuits, and will establish a basis for the development of therapies to promote regeneration of injured neurons. The computational models developed in this project will be useful for the analysis of a variety of other multi-signal, biological systems. PROJECT/

项目总监/首席研究员（最后、第一、中间）：HONG, KYONSOO 项目摘要（参见说明）： 生长锥导航至目标对于神经回路的建立至关重要 系统开发。生长锥位于生长神经突的尖端，可穿过各种细胞外细胞 他们必须感知、整合和响应无数信号的环境。该项目旨在 研究生长锥所需的多信号通路整合的分子机制 正常神经系统发育期间的指导。这些多信号交互的复杂性 生长锥引导过程中的途径，例如一致检测和串扰信号传导，以及它们的 发育过程中的时空变化阻碍了仅通过生物学方法对其进行阐明。目标是 该项目旨在将生物学家和计算科学家聚集在一起，以确定其机制 由多个神经递质引导信号引起的神经元活动在突触接触之前被转导 使用完善的实验方法和先进的计算分析建立。 我们的目标是通过实验研究内在生长锥特性的发育变化 确定生长锥对外部信号（即离子通道和神经递质信号）的反应，并 将它们编码到一个计算模型中，该模型可以模拟发生在的正常生长锥行为 体内神经系统发育过程中对外部指导信号的反应。我们将确定效果 神经递质的发育阶段依赖性变化和生长锥转向的引导信号 体外，然后在体外和体内测试它们的依赖性，并开发计算、多信号 整合和化学传感生长锥模型。多信号集成模型将用于模拟 生长锥的生物反应，以预测最具生物效率的双向引导信号 机制并预测是否有足够的数据来忠实地表示生长锥 多信号整合以充分描述体内发生的正常生长锥迁移。化学传感 模型将用于解码生长锥在生长期间遇到的外部环境化学梯度 他们在体内的指导，并预测生长锥行为所需的基本环境参数 让他们通过直接实验来确认。 相关性（参见说明）： 我们的实验研究和计算模型共同将广泛影响我们对 建立功能性神经回路所需的多信号机制，并将为 开发促进受损神经元再生的疗法。开发的计算模型 该项目将有助于分析各种其他多信号生物系统。 项目/