The Role of a Pair of MAP3Ks in the Multicellular Response to Spinal Cord Injury

项目总结/摘要 脊髓损伤后，过多的细胞反应影响功能恢复。神经元可以被保存下来 或经历细胞死亡、轴突变性和/或再生尝试。星形胶质细胞可能变得肥大， 封闭损伤中心并以复杂的方式影响轴突反应。其他细胞类型，如 成纤维细胞/周细胞、小胶质细胞、巨噬细胞也起重要作用。了解不同的细胞类型 如何调节它们的反应以及它们如何促进功能恢复是至关重要的 用于开发治疗干预以促进脊髓损伤后的功能修复。再生 轴突从损伤的神经元生长，而出芽是轴突从未损伤的神经元生长。两者可以 有助于功能恢复。DLK和LZK是无脊椎动物DLK的哺乳动物同系物， 在C.线虫和果蝇。哺乳动物DLK的作用 而LZK在脊髓修复中的作用尚不清楚。在这个父R 01的支持下，我们的实验室发现LZK在以下方面的作用： 星形胶质细胞的反应，并且现在已经确定了DLK和LZK在轴突修复中的神经元作用。这种补充剂 旨在支持一个来自代表性不足的背景的研究生，他要求重要的 关于DLK和LZK在神经元对损伤的反应中的上下文依赖性作用的问题。具体而言是 受训者将使用发生显著细胞死亡的损伤模型来询问是否相同的sinaling 在相同的细胞水平上，在不同的损伤模式下， 神经元型然后，对DLK/LZK操纵的神经元的转录谱分析将鉴定潜在的 信号通路的下游效应物。总之，这些实验提供了巨大的培训潜力， 学生，并补充现有的实验提出了在家长R 01，而其余的内 原始应用程序的总体目标。从拟议的研究的见解将铺平道路， 针对这些分子的开发，以促进脊髓损伤后的修复和恢复。

PROJECT SUMMARY / ABSTRACT After spinal cord injury, a plethora of cellular responses impact functional recovery. Neurons may be preserved or undergo cell death, axon degeneration and/or regenerative attempt. Astrocytes may become hypertrophic, seal off the injury epicenter and influence axonal response in complex ways. Other cell types such as fibroblasts/pericytes, microglia, macrophages also play important roles. Understanding how different cell types respond to injury, how their responses are regulated and how they contribute to functional recovery is critical for developing therapeutic intervention to promote functional repair after spinal cord injury. Regeneration is axonal growth from injured neurons and sprouting is axonal growth from uninjured neurons. Both may contribute to functional recovery. DLK and LZK are mammalian homologues of invertebrate DLK that has been shown to play important roles in axon regeneration in C. elegans and Drosophila. The role of mammalian DLK and LZK in spinal cord repair was not known. Supported by this parent R01, our lab found a role for LZK in astrocyte response, and have now identified neuronal roles for DLK and LZK in axonal repair. This supplement aims to support a graduate student from an underrepresented background, who is asking the important questions on the context-dependent roles of DLK and LZK in neuronal response to injury. Specifically, the trainee will use an injury model where significant cell death occurs to interrogate whether the same sinaling pathway can influence both axon regeneration and cell death under different injury paradigms on the same neuronal type. Transcriptional profiling on DLK/LZK manipulated neurons will then identify potential downstream effectors of the signaling pathway. Together, these experiments offer great training potential for the student, and complements the existing experiments proposed in the parent R01 while remaining within the overall goal of the original application. Insights from the proposed study will pave the way for therapeutic development targeting these molecules to promote repair and recovery after spinal cord injury.