The Role of Actomyosin in Response to Injury and Myelin

描述(由申请人提供)：神经系统损伤会降低 伤者的生活质量。因此，当务之急是 开发治疗方法，旨在改善和预防 对神经系统的损害。治疗方法的合理发展需要 关于神经元对损伤的反应的具体知识。在受伤期间，神经 纤维经常受到损伤，并通过回缩做出反应。神经的回缩 纤维导致神经元群体之间失去连通性， 表现为功能障碍(例如，失去运动控制和 感觉)。损伤组织中神经纤维的回缩不利于 神经系统的功能，最初发生在对直接的物理反应 损伤，并随后对髓磷脂衍生的抑制信号做出反应 对伤害的反应而发展。因此，重要的是要了解 神经纤维回缩的细胞机制 合理的治疗方法。将追求三个目标来测试 假设神经纤维收缩是对身体损伤的反应 髓鞘衍生的抑制信号共享一个共同的机制，即 肌动球蛋白依赖的收缩能力。 目的1.阐明细胞骨架在损伤诱导的神经纤维中的作用 撤回。被切断的神经纤维的细胞骨架将是 研究以确定它如何在受伤后重新组织。的作用 肌动蛋白细丝和微管在损伤诱导的神经纤维回缩中的作用 也要有决心。 目的2.确定肌动球蛋白的收缩能力在收缩过程中的作用 神经纤维被切断。许多技术将被用来干扰 肌动球蛋白的功能，并研究这些治疗是如何影响收缩的 神经纤维。已知的调节肌动蛋白功能的酶系统的作用 也将接受调查。 目的3.确定肌动球蛋白在神经反应中的作用 纤维对髓鞘衍生的抑制信号。与目标2类似， 抑制肌动球蛋白对髓鞘诱导的轴突收缩的作用将是 调查过了。这些研究将使用背根神经节神经元，一个群体 将神经纤维送入脊髓的神经元。对神经的损伤 脊髓中这些神经元的纤维会导致感觉丧失。 和本体感觉。体外回缩的细胞学基础将被研究 用实时视频显微镜直接测定神经的反应 纤维。将使用多种方法来抑制该酶的活性 肌动球蛋白系统及其抑制肌动球蛋白的新途径 将开展活动。总而言之，这些研究将决定 肌动球蛋白系统是开发有针对性的治疗方法的可行靶点。 抑制受损神经组织中的神经纤维回缩。

DESCRIPTION (provided by applicant): Injury to the nervous system decreases the quality of life of the injured individual. Therefore, it is a priority to develop therapeutic approaches aimed at the amelioration and prevention of damage to the nervous system. The rational development of therapies requires a concrete knowledge of the response of neurons to injury. During injury, nerve fibers are often damaged and respond by retracting. The retraction of nerve fibers results in the loss of connectivity between neuronal populations that manifests as functional disabilities (e.g., loss of motor control and sensation). The retraction of nerve fibers in injured tissue is detrimental to nervous system function and occurs initially in response to direct physical damage, and subsequently in response to myelin-derived inhibitory signals that develop in response to injury. Therefore, it is important to understand the cellular mechanisms involved in nerve fiber retraction in order to develop rational therapeutic approaches. Three aims will be pursued to test the hypothesis that nerve fiber retraction in response to physical injury and myelin-derived inhibitory signals share a common mechanism requiring actomyosin-dependent contractility. Aim 1. Elucidate the role of the cytoskeleton in injury-induced nerve fiber retraction. The cytoskeleton of nerve fibers that have been severed will be studied to determine how it reorganizes in response to injury. The role of actin filaments and microtubules in injury-induced nerve fiber retraction will also be determined. Aim 2. Determine the role of actomyosin contractility in the retraction of severed nerve fibers. A number of techniques will be used to interfere with actomyosin function and study how these treatments affect the retraction of nerve fibers. The role of enzyme systems known to regulate actomyosin function will also be investigated. Aim 3. Determine the role of actomyosin contractility in the response of nerve fibers to myelin-derived inhibitory signals. Similar to aim 2, the effects of inhibiting actomyosin function on myelin-induced axon retraction will be investigated. These studies will use dorsal root ganglion neurons, a population of neurons that sends nerve fibers into the spinal cord. Damage to the nerve fibers of these neurons in the spinal cord can result in the loss of sensation and proprioception. The cellular basis of retraction in vitro will be studied using live video microscopy to directly determine the responses of nerve fibers. A number of methods will be used to inhibit the activity of the actomyosin system, and novel approaches to the inhibition of actomyosin activity will be developed. Collectively, these studies will determine whether the actomyosin system is a viable target for the development of therapies aimed at the inhibition of nerve fiber retraction in injured nervous tissue.