CRCNS: Activity-dependent growth cone guidance

描述(由申请人提供)：在神经系统发育过程中，将生长锥体导航到其目标位置对于建立神经回路是必不可少的。生长锥体位于生长中的轴突的顶端，它们必须在各种细胞外环境中导航，在这些环境中它们必须感知、整合和响应无数的信号。该项目旨在研究在正常神经系统发育过程中生长锥引导所需的多个信号通路整合的分子机制。这些多信号通路在生长锥引导过程中相互作用的复杂性，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，使得仅用生物学方法无法阐明它们。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，确定在突触联系建立之前，由多个神经递质引导信号引起的神经元活动被转导的机制。我们的目标是从实验上研究决定生长锥对外部信号(即离子通道和神经递质信号)反应的内在生长锥特性的发育变化，并将其编码到一个计算模型中，该模型可以模拟在活体神经系统发育过程中响应外部指导信号而发生的正常生长锥行为。我们将在体外确定神经递质和引导信号随发育阶段的变化对生长锥转动的影响，随后在体外和体内检验它们的相关性，并建立计算、多信号集成和化学传感生长锥模型。多信号整合模型将被用于模拟生长锥的生物反应，预测生物学上最有效的双向引导信号机制，并预测是否有足够的数据来真实地表示生长锥多信号整合，以全面描述发生在体内的正常生长锥迁移。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。

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.