The role of a pair of MAP3Ks in the multicellular response to spinal cord injury

项目摘要/摘要 脊髓损伤后，过多的细胞反应影响功能恢复。神经元可能被保存下来 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， 封闭损伤震中，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、巨噬细胞也发挥重要作用。了解不同类型的细胞如何 对损伤的反应，他们的反应如何被调节，以及他们如何对功能恢复做出贡献是至关重要的 开发治疗干预措施，促进脊髓损伤后的功能修复。再生是 损伤神经元的轴突生长和发芽就是未损伤神经元的轴突生长。两者都可能 有助于功能恢复。DLK和LZK是无脊椎动物DLK的哺乳动物同源物，DLK已经被 研究表明在线虫和果蝇的轴突再生中起着重要作用。哺乳动物DLK的作用 而LZK在脊髓修复中的作用尚不清楚。在研究DLK(MAP3K12)和LZK(MAP3K13)的过程中 在脊髓损伤后轴突修复方面，我们的实验室已经确定了LZK在星形细胞瘢痕形成中的关键作用。这 结果与已发表的关于STAT3和PTEN的文献相印证，说明了一个新兴的主题，即信号 调节轴突修复的途径也可能调节星形胶质细胞对损伤的反应。在这份补充提案中， 我们将利用一系列诱导物研究LZK在脊髓损伤和修复中的星形胶质细胞特异性作用。 功能小鼠遗传品系的得失。我们将绘制LZK与另一个已知信号的相互作用图 STAT3参与星形胶质细胞反应调控的途径，决定转录的变化和功能 操纵这些通路的后果。总之，这些研究将有助于理解 星形胶质细胞的反应是如何调节的，以及它如何在直接和间接的 间接的方式，后者通过影响轴突的修复。这样的理解将为 针对这些分子的治疗进展，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 in not known. In the process of studying DLK (MAP3K12) and LZK (MAP3K13) in axonal repair after spinal cord injury, our lab has identified a critical role for LZK in astrocytic scarring. This result corroborates with published literature on Stat3 and Pten to illustrate an emerging theme that signaling pathways regulating axonal repair may also regulate astrocyte response to injury. In this supplement proposal, we will investigate the astrocyte specific roles of LZK in spinal cord injury and repair using an array of inducible loss and gain of function mouse genetic lines. We will map the interaction of LZK with another known signaling pathway involving Stat3 in regulating astrocyte response, determine the transcriptomic changes and functional consequences of manipulating these pathways. Together, these studies will contribute to the understanding of how the astrocyte response is regulated and how it contributes to repair and recovery in both a direct and indirect manner, the latter through the effect on axonal repair. Such understanding will pave the way for therapeutic development targeting these molecules to promote repair and recovery after spinal cord injury.