CRCNS: Activity-dependent growth cone guidance

项目主任/首席调查员(最后、第一、中间)：Hong，Kyonsoo 项目总结(见说明)： 在神经活动过程中，将生长锥体导航到它们的靶点对于建立神经回路至关重要。 系统开发。生长锥体位于生长中的轴突的顶端，穿过各种细胞外的 在这样的环境中，他们必须感知、整合和回应无数的信号。这一项目旨在 研究生长锥所需多条信号通路整合的分子机制 在正常神经系统发育期间的指导。这些多信号相互作用的复杂性 生长锥体引导期间的路径，如重合检测和串扰信号，以及它们的 发育过程中的时空变化，阻碍了仅用生物学方法来阐明它们。的目标是 这个项目是将生物学家和计算科学家聚集在一起，以确定 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传递 利用成熟的实验方法和先进的计算分析，建立了。 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的反应，即离子通道和神经递质信号，并 将它们编码到计算模型中，该模型可以模拟发生在 在活体神经系统发育过程中对外部引导信号的反应。我们将确定其影响 生长锥体内神经递质和引导信号随发育阶段的变化 在体外，随后在体外和体内测试它们的依赖性，并开发计算、多信号 集成和化学敏感生长锥体模型。将使用多信号集成模型来模拟 生长锥体的生物反应，以预测生物最有效的双向引导信号 机制，并预测是否有足够的数据以允许真实地表示生长锥体 多信号积分，以全面描述发生在体内的正常生长锥迁移。化学传感 模型将被用来解码生长锥在生长过程中遇到的外部环境化学梯度 它们在体内的指导，并预测生长锥行为所需的基本环境参数 允许通过直接实验来证实它们。 相关性(请参阅说明)： 我们的实验研究和计算模型一起，将广泛影响我们对 建立功能神经回路所需的多种信号机制，并将为 促进受损神经元再生的治疗方法的发展。中开发的计算模型 该项目将对各种其他多信号、生物系统的分析有用。 项目/

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/