Modeling and analysis of material transport in complex geometry of neurons

为了生存和发挥功能，神经元必须将必要的物质向下运输被称为神经突起的长投射。轴突将信息传递给其他神经元，并从其他神经元传递信息。必须控制材料沿神经突起的运输，以确保将正确的类型和数量的材料运送到正确的目的地。使用新的工程模型、方法和软件，该项目的目标是解释材料交通是如何在复杂的神经元几何结构中进行路由和平衡的。这将加深对神经元如何运作其物质运输系统的了解，更重要的是，如何控制神经元的结构和功能。该项目的成功完成将1)促进神经生物学和神经工程的基础知识，了解如何在复杂的神经元几何结构中运输材料；2)提供与阿尔茨海默病等神经疾病相关的材料运输机制的新见解；3)生产开发相关药物输送解决方案所需的软件。开发的工程工具将自由和开放地分发，以进一步促进相关的基础研究和翻译研究。该项目的研究将与教学紧密结合，为学生提供跨学科的培训机会。与神经生物学和神经工程基本知识相关的教育材料将通过互联网以及当地的教育和推广活动开发并向公众传播。该项目的目标是通过开发和应用新的工程模型、方法和软件，阐明材料运输如何在复杂的神经元几何结构中进行路由和平衡。研究旨在验证基于复杂轴突网络的局部几何形状主动控制流量路由和平衡的假设。该研究计划有三个目标。1)确定流量如何在轴心网络内进行路由。通过收集果蝇感觉神经元和大鼠海马神经元轴突交界处淀粉样前体、突触囊泡蛋白和线粒体运输的延时图像，并对进入不同分支的货物进行计数，可以获得网络的几何和运输模式。数据分析功能包括开发轴突跟踪软件，对每个分支的交通路线分布进行向量表征，基于对交叉口细胞骨架结构的不同假设测试不同的交通路线模型，以及使用单个粒子跟踪。然后，开发的成像和数据分析技术将被应用于确定特定轴突分支的损伤(激光消融)和阿尔茨海默氏症(淀粉样β蛋白诱导的)是否会影响交通路线。2)确定如何在轴突网络中平衡流量。网络的拓扑结构将用树来表示，代谢网络的流量平衡分析将启发理解流量平衡的理论框架。重点将放在如何在单个分支机构和子网络中平衡流量。与目标1类似，将进行研究以确定受损和阿尔茨海默病神经元的交通是如何平衡的。将使用计算机模拟来了解流量路由和平衡之间的关系。3)开发和应用开源软件，用于复杂的神经元三维几何结构中物质输运的计算机模拟。一种新的基于等几何分析(IGA)的数值技术将被开发来模拟复杂几何形状内的材料输运。该模拟软件将通过与实验相结合的方式进行验证和测试，然后用于设计相关神经疾病的细胞内给药策略，其几何形状可以在现有数据库中获得。该项目的成果有可能推动神经生物学和神经工程领域的发展；神经生物学的进展来自于对神经元结构和功能的新理解；神经工程学的进展来自于对如何利用和控制材料运输过程的新理解，用于修复和更新受损或退化的神经元。开发的图像采集、数据分析和建模工具可能广泛适用于其他调查领域。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

To survive and function, neurons must transport essential materials down long projections called neurites. Neurites bring information to and from other neurons. The transport of materials down neurites must be controlled to make sure that the right type and amount of material is delivered to the right destination. Using new engineering models, methods, and software, this project's goal is to explain how material traffic is routed and balanced in the complex geometry of neurons. This will enhance understanding of how neurons operate their material transport systems and, more importantly, how to control neuronal structure and function. Successful completion of this project will 1) advance fundamental knowledge of neurobiology and neural engineering on how materials are transported in the complex geometry of neurons; 2) provide new insights into mechanisms of material transport related to neurological diseases such as Alzheimer's disease; and 3) produce software required for developing related drug delivery solutions. The engineering tools developed will be distributed freely and openly in order to further advance related basic and translational research. Research in this project will be closely integrated with teaching to provide students with interdisciplinary training opportunities. Educational materials related to basic knowledge of neurobiology and neural engineering will be developed and disseminated to the public through the internet as well as through local education and outreach activities.The goal of this project is to elucidate how material transport traffic is routed and balanced in the complex geometry of neurons through developing and applying new engineering models, methods and software. Studies are designed to test the hypothesis that traffic routing and balancing are actively controlled based on the local geometry of the complex neurite network. The research plan has three aims. 1) To determine how traffic is routed within the neurite network. Network geometry and transport patterns will be obtained by collecting time-lapse movies of transport of amyloid precursor and synaptic vesicle proteins and mitochondria at neurite junctions of drosophila sensory neurons and rat hippocampal neurons and counting the number of cargoes going into different branches. Data analysis features include developing neurite tracing software, vector characterization of traffic routing distributions at each branch, testing different traffic routing models based on different assumptions of the cytoskeletal structure at the junctions, and using single particle tracking. The imaging and data analysis techniques developed will then be applied to determining if damage of specific neurite branches (laser ablation) and the Alzheimer's condition (amyloid-beta peptide induced) will influence traffic routing. 2) To determine how traffic is balanced within the neurite network. The topological structure of the network will be represented as trees and the theoretical framework for understanding traffic balance will be inspired by flux balance analysis of metabolic networks. The focus will be on how traffic is balanced in single branches and subnetworks. Comparable to Aim 1, studies will be performed to determine how traffic is balanced in damaged and Alzheimer's disease neurons. Computer simulations will be used to understand relations between traffic routing and balancing. 3) To develop and apply open-source software for computer simulation of material transport in complex 3D geometry of neurons. A new isogeometric analysis (IGA) based numerical technique will be developed to simulate material transport within the complex geometry. The simulation software will be validated and tested through integration with experiments and then used to design intracellular delivery strategies for related neurological diseases whose geometries can be obtained in existing databases. The results of this project have the potential to advance both neurobiology and neuroengineering fields; neurobiology advances come in the form of new understanding of the structure and function of neurons; neuroengineering advances come in the form of new understanding about how to utilize and control the material transport process for applications such as repair and renewal of damaged or degenerative neurons. The image acquisition, data analysis and modeling tools developed may be widely applicable in other areas of investigation.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.