Dissecting the molecular pathways controlling axon degeneration after injury

描述（申请人提供）：外周感觉轴突损伤后的退行性变是一个由特定的内在和外在通路调节的主动过程。我对了解外周轴突退化和再生的机制很感兴趣，这具有重要的临床意义，但很难在人类患者中进行细胞或分子分辨率的研究。我们建立了一个模型来研究活斑马鱼胚胎的感觉轴突退化。斑马鱼是研究神经元发育的一个很好的模型，因为它们是外部受精的，发育迅速，受精后几天保持透明，可以实时观察活体神经元重塑的整个过程。

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