Collaborative Research: Dynamic Regulation of Axonal Morphology by Neurofilament Transport

神经细胞延伸出又长又细的突起，称为轴突，它定义了神经系统的连接模式。轴突允许神经细胞彼此之间以及与全身其他细胞进行电子通信。每个轴突都包含一个微小的、内部充满空间的蛋白质支架，称为神经丝，分子马达蛋白不断地沿着轴突穿梭；这些蛋白质定义了轴突的形状和大小。神经丝在发育过程中积累，增加轴突直径，使电活动更快地传播；过度积累(如许多神经退行性疾病中所发生的)可导致沟通异常和轴突退化。这个项目测试了神经丝运输速度决定轴突直径、形状和功能的假设。这项工作将由一个由生物学家和物理学家组成的经验丰富的跨学科团队进行，将创新的生物成像技术与数学和计算方法相结合，以研究这些重要问题。从这项研究中获得的见解将对理解健康的大脑功能至关重要，也可能为许多神经退行性疾病中观察到的轴突问题提供重要的见解。来自物理科学和生命科学的这一项目的受训人员将在首席研究人员的监督下工作，并将通过跨学科互动扩大他们的技能，增加物理科学和生命科学交界处的熟练研究队伍。为了将拟议研究的影响扩展到K-12水平，参与该项目的物理学家和生物学家将主办有重点的小组研讨会，寻求赋予初中和高中教师在细胞生物学和算法思维领域的想法和工具，以促进他们在细胞生物学和算法思维领域的教学，并引入他们可以在课堂上应用的免费但强大的学习工具。神经系统的功能取决于动作电位沿着轴突以特定于其生理功能的速度传播。这一速度取决于轴突的大小和形状。脊椎动物轴突大小和形状的主要决定因素是被称为神经丝的充满空间的细胞骨架聚合物。神经丝也是轴突运输的货物，沿着微管轨道移动。因此，神经细丝决定了轴突的形态，但它们也处于恒定的流动中。这项拟议的研究解决了这种耐人寻味的生理上重要的关系。中心假设是神经丝运输的动力学决定了轴突神经丝的含量，而轴突的含量又决定了轴突的口径和功能。具体目标是确定神经丝运输速度和流量之间的动态相互作用，以及神经丝如何在Ranvier结节的局部狭窄中导航。为了实现这些目标，研究人员将采用计算和数学方法的紧密结合，并在体外对一种在神经元中表达可光激活神经丝蛋白的新型转基因小鼠的周围神经有髓轴突进行创新的实时成像。

Nerve cells extend long, thin protrusions called axons that define the wiring pattern of the nervous system. Axons allow nerve cells to communicate electrically with each other and with other cells throughout the body. Each axon contains a microscopic, internal scaffold of space-filling proteins called neurofilaments that are constantly shuttled along the axon by molecular motor proteins; these define axon shape and size. Neurofilaments accumulate during development, increasing axon diameter and allowing electrical activity to travel more quickly; excessive accumulation (as occurs in many neurodegenerative diseases) can lead to communication abnormalities and axonal degeneration. This project tests the hypothesis that the rate of neurofilament transport determines the diameter, shape and function of axons. The work will be conducted by a seasoned interdisciplinary team of biologists and physicists, combining innovative biological imaging techniques with mathematical and computational methods to investigate these important questions. The insights gained from this research will be critical for understanding healthy brain function and could also provide important insights into the axonal problems observed in many neurodegenerative diseases. Trainees on this project from both the physical and life sciences will work in teams supervised by the principal investigators, and will expand their skills through interdisciplinary interaction, adding to the skilled research workforce at the interface of the physical and life sciences. To extend the impact of the proposed research to the K-12 level, the physicists and biologists on this project will host focused, small-group workshops that will seek to empower middle and high school teachers with ideas and tools to invigorate their instruction in the areas of cell biology and algorithmic thinking, and introducing freely available but powerful learning tools that they can apply in their classrooms.The function of nervous systems is dependent on the propagation of action potentials along axons at a velocity that is specific to their physiological function. This velocity is dependent on axon size and shape. A principal determinant of axon size and shape in vertebrates are space-filling cytoskeletal polymers called neurofilaments. Neurofilaments are also cargoes of axonal transport that move along microtubule tracks. Thus, neurofilaments define axonal morphology, but they are also in constant flux. The proposed research addresses this intriguing and physiologically important relationship. The central hypothesis is that the kinetics of neurofilament transport determines axonal neurofilament content, which in turn specifies axonal caliber and function. The specific goals are to determine the dynamic interplay between neurofilament transport velocity and flux in the specification of overall axon caliber, and how neurofilaments navigate local constrictions at the nodes of Ranvier. To accomplish these goals, the investigators will employ a tight integration of computational and mathematical methods with innovative live imaging of myelinated axons in peripheral nerves ex vivo from a new transgenic mouse that expresses a photoactivatable neurofilament protein in neurons.