REGULATION OF AXONAL DEGENERATION BY THE DLK KINASE

 描述（由申请人提供）：神经元损伤和疾病是患者、家庭和社会的巨大负担。改善神经系统疾病的治疗将需要更好地了解神经元如何对病理损伤作出反应，以便操纵这些反应以获得治疗益处。轴突是神经回路中特别脆弱的组成部分，在许多神经系统疾病中受损。对于损伤或疾病，存在三种对轴突损伤的主要神经元反应：1）轴突可经历轴突变性的受调节的自毁机制，2）在外周神经系统中，神经元可激活可导致轴突再生的轴突生长程序，以及3）受损的神经元可死亡。MAP3K双亮氨酸拉链激酶（DLK）是每种神经元对损伤、轴突变性、轴突再生和神经元细胞死亡的反应的关键调节剂。DLK在神经元对损伤的反应中的中心作用导致了以下假设：DLK是轴突损伤的关键传感器，将该信号转导至细胞的其余部分，在那里它可以触发退行性、再生和凋亡反应。虽然很明显DLK在轴突损伤反应途径中起着开创性的作用，但为了确定靶向DLK的治疗潜力，仍然存在许多悬而未决的问题。首先，DLK如何促进损伤的再生和退行性反应？了解这些机制可能有助于有选择地操纵这些结果。第二，虽然DLK对于轴突损伤后再生程序的诱导是必需的，但是不知道DLK的激活是否足以在没有损伤的情况下激活该程序，或者是否足以增强损伤后的再生能力。PNS再生的改善将具有重要的临床结果，因为内源性再生的缓慢速度是功能恢复的关键障碍。最后，什么机制调节DLK信号传导？调节DLK依赖性信号传导的蛋白质的鉴定将产生用于患病或受损神经系统的新的治疗靶标。如果成功，这项工作将大大推进我们对DLK通路的功能，调节和治疗潜力的理解。

 DESCRIPTION (provided by applicant): Neuronal injury and disease are a huge burden to patients, families, and society. Improved treatments for neurological disorders will require a better understanding of how neurons respond to pathological insults in order to manipulate these responses for therapeutic benefit. Axons are a particularly vulnerable component of neural circuits that are damaged in many neurological diseases. With injury or disease, there are three primary neuronal responses to axon injury: 1) the axon may undergo a regulated self-destruction mechanism of axonal degeneration, 2) in the peripheral nervous system the neuron may activate an axonal growth program that can result in axonal regeneration, and 3) the injured neuron may die. The MAP3K Dual leucine zipper kinase (DLK) is a key regulator of each neuronal response to injury, axon degeneration, axon regeneration, and neuronal cell death. The central role of DLK in the neuronal response to injury leads to the hypothesis that DLK is a key sensor of axonal injury, transducing that signal to the remainder of the cell where it may trigger degenerative, regenerative, and apoptotic responses. While it is clear that DLK plays a seminal role in the axonal injury response pathway, numerous open questions remain that must be addressed in order to define the therapeutic potential of targeting DLK. First, how does DLK promote both regenerative and degenerative responses to injury? Understanding these mechanisms could be useful for selectively manipulating these outcomes. Second, while DLK is necessary for induction of the regenerative program following axon injury, it is not known whether activation of DLK is sufficient to activate this program in the absence of injury, or to enhance the regenerative capacity following injury. Improvements to regeneration in the PNS would have important clinical consequences, since the slow pace of endogenous regeneration is the key obstacle to functional recovery. Finally, what mechanisms regulate DLK signaling? Identification of proteins that modulate DLK- dependent signaling will generate novel therapeutic targets for the diseased or injured nervous system. If successful, this work will significantly advance our understanding of the function, regulation, and therapeutic potential of the DLK pathway.