Dissecting the molecular pathways controlling axon degeneration after injury

剖析损伤后控制轴突变性的分子途径

• 批准号: 8071110
• 负责人: Seanna Marie Martin
• 金额: $ 3.24万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-07-01 至 2011-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8071110
• 关键词: Acute; Affect; Afferent Neurons; Apoptosis; Axon; Axotomy; Cells; Clinical; Distal; Embryo; Environment; Fertilization; Genetic; Head; Human; Image; Injury; Knowledge; Lasers; Life; Modeling; Molecular; Natural regeneration; Nature; Neuroglia; Neurons; Organism; Pathway interactions; Patients; Peripheral; Peripheral Nerves; Phagocytes; Phase; Play; Process; Production; Resolution; Role; Sensory; Skin; Study models; System; Techniques; Testing; Time; Touch sensation; Trigeminal System; Ubiquitin; Wallerian Degeneration; Zebrafish; improved; injured; insight; interest; macrophage; multicatalytic endopeptidase complex; neuron development; neuronal cell body; prevent; repaired; response

DESCRIPTION (provided by applicant): The degeneration of peripheral sensory axons after injury is an active process regulated by specific intrinsic and extrinsic pathways. I am interested in understanding the mechanisms of peripheral axon degeneration and regeneration, which have important clinical implications but are difficult to study with cellular or molecular resolution in human patients. We have developed a model to study sensory axon degeneration in live zebrafish embryos. Zebrafish are an excellent model for studying neuronal development since they are fertilized externally, develop quickly, and remain transparent for several days post-fertilization, allowing the entire process of neuronal remodeling to be observed in real time in a live organism. Following injury to peripheral sensory axons, the distal portion of the axon that is no longer connected to the cell body quickly breaks down by a process called Wallerian degeneration. The rapid nature of the fragmentation and debris clearance implies that genetic pathways or external influences are responsible for instigating this active response. Our precise laser axotomy technique paired with time-lapse confocal imaging allows for detailed, quantitative analysis of the process of axon degeneration. By understanding and altering the mechanisms of degeneration, it may be possible to improve the ability of an injured axon to regenerate and occupy its previous territory. Alternatively, preventing degeneration from occurring altogether may allow an injured axon to be repaired, thus restoring its function. Any new molecular pathways discovered that affect degeneration could potentially inspire therapies for patients with peripheral nerve damage or acute injury. This proposal focuses primarily on the degeneration of peripheral sensory axons of trigeminal sensory neurons, touch-sensing neurons that innervate the head. Specific Aim 1: To determine the intrinsic pathways controlling axon degeneration in different contexts Specific Aim 2: To identify the phagocytes responsible for removing axonal debris in different environments

描述(申请人提供)：损伤后周围感觉神经轴突的退化是一个由特定的内在和外在途径调节的活跃过程。我对了解外周轴突变性和再生的机制很感兴趣，这些机制具有重要的临床意义，但在人类患者中很难用细胞或分子分辨率进行研究。我们开发了一个模型来研究活斑马鱼胚胎的感觉轴突变性。斑马鱼是研究神经元发育的优秀模型，因为它们在体外受精，发育迅速，受精后几天保持透明，允许在活体中实时观察神经元重塑的整个过程。 外周感觉轴突受损后，不再与细胞体相连的轴突远端部分通过一种称为沃勒变性的过程迅速分解。碎片和碎片清除的快速性质意味着遗传途径或外部影响负责激发这种积极的反应。我们的精密激光轴突切断术与延时共聚焦成像相结合，可以对轴突变性过程进行详细、定量的分析。通过了解和改变退变的机制，有可能提高受损轴突再生和占据其先前领土的能力。或者，防止完全发生变性可能会修复受损的轴突，从而恢复其功能。任何新发现的影响退变的分子通路都可能启发周围神经损伤或急性损伤患者的治疗。这项建议主要关注三叉神经感觉神经元的外周感觉轴突的退化，三叉神经感觉神经元是支配头部的触觉神经元。 特定目标1：确定在不同环境中控制轴突变性的内在途径特定目标2：确定在不同环境中负责清除轴突碎片的吞噬细胞