CRCNS: Activity-dependent growth cone guidance

CRCNS：活动依赖性生长锥指导

• 批准号: 7615891
• 负责人: KYONSOO HONG
• 金额: $ 37.06万
• 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/7615891
• 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; Interneurons; Intracellular Second Messenger; Ion Channel; Ligands; Measures; Membrane Potentials; Methods; Modeling; Molecular; Monitor; Nervous system structure; Neurites; Neurons; Neurotransmitter Receptor; Neurotransmitters; Principal Investigator; Property; Protein Overexpression; Proteins; Reporting; Scientist; Second Messenger Systems; Semaphorin-3A; Signal Pathway; Signal Transduction; Simulate; Site; Spinal; Staging; Synapses; Testing; Whole-Cell Recordings; Xenopus; base; environmental chemical; extracellular; human NTN1 protein; in vivo; migration; nervous system development; netrin-1; neural circuit; neurotransmitter release; prevent; receptor; response; spatiotemporal; trafficking; voltage

DESCRIPTION (provided by applicant): 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 of extracellular 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.

描述（由申请人提供）：在神经系统发育过程中，生长锥的导航对神经回路的建立至关重要。生长锥体位于生长中的神经突的尖端，在各种细胞外环境中导航，它们必须感知、整合和响应无数的信号。本项目旨在研究正常神经系统发育过程中生长锥引导所需的多信号通路整合的分子机制。在生长锥引导过程中，这些多信号通路相互作用的复杂性，如重合检测和串扰信号，以及它们在发育过程中的时空变化，阻碍了它们仅通过生物学方法来阐明。该项目的目标是将生物学家和计算科学家聚集在一起，利用成熟的实验方法和先进的计算分析，确定在突触接触建立之前，由多种神经递质引导信号引起的神经元活动被转导的机制。我们的目的是通过实验研究生长锥内在特性的发育变化，这些特性决定了生长锥对外部信号（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，该模型可以模拟神经系统发育过程中正常的生长锥对外部引导信号的反应。我们将确定发育阶段依赖的神经递质和引导信号变化对体外生长锥转向的影响，随后在体外和体内测试它们的依赖性，并开发计算、多信号集成和化学传感生长锥模型。多信号整合模型将用于模拟生长锥的生物反应，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的多信号整合，以充分描述正常生长锥在体内发生的迁移。化学传感模型将用于解码生长锥在体内引导过程中遇到的外部环境化学梯度，并预测生长锥行为所需的基本环境参数，以便通过直接实验进行确认。