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Regenerative and degenerative responses to axonal injury

对轴突损伤的再生和退行性反应

基本信息

批准号：
10263459
负责人：
CATHERINE A COLLINS
金额：
$ 54.6万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-30 至 2021-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10263459
关键词：
Acute Alzheimer&apos s Disease Animal Model Ankyrins Astrocytes Axon Axonal Transport Brain CCR5 gene Categories Cell physiology Cells Collaborations Cytoskeleton Data Defect Disease Drosophila genus Excision Future Genes Genetic Glaucoma Goals Homologous Gene Image Immune Immune response Immune system Inflammation Injury Lead Light Location Methods Microglia Mitogen-Activated Protein Kinases Modeling Molecular Motor Neurons Mus Natural regeneration Nerve Nerve Degeneration Nervous System Trauma Nervous system structure Neurodegenerative Disorders Neuroglia Neuroimmune Neuromuscular Junction Neuronal Injury Neurons Neuropathy Operative Surgical Procedures Optic Nerve Outcome Pathway interactions Peripheral nerve injury Phenotype Phosphotransferases Presynaptic Terminals Proteins Public Health Recovery Regulation Retinal Ganglion Cells RiboTag Rodent Schwann Cells Sensory Signal Transduction Spectrin Spinal Sternocleidomastoid Muscle Stress Stroke Synapses Technology Testing Therapeutic Wallerian Degeneration Work axon injury axon regeneration base biological adaptation to stress cell type chemotherapy excitotoxicity extracellular fly functional outcomes injured mechanical allodynia mouse model nerve injury neuron loss neuronal cell body presynaptic recruit regenerative repaired response restraint stathmin tool translatome

项目摘要

Project Summary/Abstract: Axons form connections between neurons over great distances in the brain and body, hence are vulnerable to damage and stress. This project studies an evolutionarily conserved stress response pathway that becomes activated in multiple scenarios of damage and stress, including nerve damage, traumatic axonal injury, disruption of axonal cytoskeleton, axonal transport, and mouse models of ALS and Alzheimer's Disease. The pathway, governed by the dileucine zipper kinase DLK, known as Wallenda (Wnd) in Drosophila, promotes dichotomous outcomes of neuronal death, degeneration and regeneration in these diverse scenarios. The long term goals of this project are (1) to understand the mechanisms that lead to DLK signaling activation, and (2) to understand the cellular pathways that are regulated by DLK. The project combines studies in both Drosophila and mice, focusing on motoneuron (MN) responses to peripheral nerve injury (PNI). For the first goal, Aim 1 tests a hypothesis, built upon observation in Drosophila, that DLK/Wnd signaling is restrained by the presence of an intact synaptic connection, hence becomes activated following synapse loss. Subaim 1a probes the mechanism of synaptic restraint using genetic tools at Drosophila neuromuscular junction (NMJ). Subaim 1b tests whether the principle is conserved for mammalian neurons, taking advantage of the accessibility of the mouse NMJ to surgical manipulations and imaging. For the second goal, Aim 2 builds from translatome profiling (using RiboTag technology) of DLK-dependent responses in mouse MNs, which identified many secreted proteins and immune molecules as targets of DLK regulation following PNI. Subaim 2a establishes a descriptive characterization of the glial and immune responses gated by DLK in injured MNs and in DRG neurons, which are also injured by PNI. Subaim 2b tests a specific hypothesis that `synaptic stripping' in which upstream synaptic inputs to damaged motoneurons are removed concomitant with a recruitment of microglia to the MN cell body, is controlled by DLK activation in the injured MN. While Aim 1 identifies specific circumstances that activate DLK signaling, Aim 2 identifies downstream cellular functions of DLK that may be broadly relevant in many paradigms of injury and stress. Together the work in these two aims is expected to shed light on the relationship of synapse loss with other responses in the nervous system (neuronal death, inflammation and plasticity) in diverse contexts of injury, neuropathies and neurodegenerative disease.

项目概要/摘要：轴突在大脑和身体中的远距离神经元之间形成连接，因此容易受到伤害和压力。该项目研究了一种进化上保守的应激反应途径，在多种损伤和应激情况下激活，包括神经损伤，创伤性轴突损伤，轴突细胞骨架的破坏、轴突运输以及ALS和阿尔茨海默病的小鼠模型。的由双亮氨酸拉链激酶DLK（在果蝇中称为Wallenda（Wnd））控制的途径促进在这些不同的情况下，神经元死亡、变性和再生的二分结果。长本项目的长期目标是（1）了解导致DLK信号激活的机制，以及（2）了解由DLK调节的细胞通路。该项目结合了对果蝇和和小鼠，重点是运动神经元（MN）对周围神经损伤（PNI）的反应。对于第一个目标，目标1 测试了一个假设，建立在果蝇的观察，即DLK/Wnd信号受到抑制的存在，因此在突触丧失后被激活。Subaim 1a探测在果蝇神经肌肉接头（NMJ）使用遗传工具的突触抑制机制。Subaim 1b 测试是否原则是保守的哺乳动物神经元，利用的可访问性，小鼠NMJ的手术操作和成像。对于第二个目标，Aim 2从translatome构建在小鼠MN中DLK依赖性应答的分析（使用RiboTag技术），其鉴定了许多分泌蛋白和免疫分子作为PNI后DLK调节的靶点。Subaim 2a建立了一个损伤MN和DRG中DLK门控的神经胶质和免疫应答的描述性表征神经元，这也是由PNI损伤。Subaim 2b测试了一个特定的假设，即“突触剥离”，其中损伤运动神经元的上游突触输入被移除，同时小胶质细胞被募集， MN细胞体由受损MN中的DLK激活控制。虽然目标1确定了具体的在激活DLK信号传导的情况下，Aim 2鉴定了DLK的下游细胞功能，在许多伤害和压力的范例中广泛相关。这两个目标的工作预计将揭示了突触丧失与神经系统中其它反应的关系（神经元死亡，炎症和可塑性）在损伤、神经病变和神经退行性疾病的不同情况下。