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。过去，我们的实验室 主要集中在神经元对损伤反应的分子控制，特别是轴突。 中枢神经系统损伤后的再生和萌发。再生是指从受损神经元和神经细胞中生长轴突 发芽是指未受损伤的神经元的轴突生长。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，已被证明在轴突中发挥重要作用 线虫和果蝇的再生。哺乳动物DLK和LZK在NOT脊髓修复中的作用 为人所知。DLK(MAP3K12)和LZK(MAP3K13)在脊髓后轴突修复中的研究进展 我们已经确定了LZK在星形细胞瘢痕形成中的关键作用。这一结果与发表的结果相印证 关于STAT3和PTEN的文献阐明了一个新的主题，即信号通路调节轴突修复 也可能调节星形胶质细胞对损伤的反应。在这项建议中，我们将全面调查 LZK和DLK在脊髓损伤多细胞反应中的神经元和星形胶质细胞特异性作用 可诱导的小鼠功能遗传系的丢失和获得的阵列。DLK和LZK的下游效应器将是 通过对神经元和星形胶质细胞的转录分析进行鉴定。职能协同或裁员将 在DLK和LZK之间进行测试，以及与其他信号通路包括STAT3和Pten的相互作用 也将接受测试。总之，这些研究将确定DLK和LZK在轴突修复中的作用 和星形胶质细胞在脊髓损伤后的反应，这可能为靶向治疗开发铺平道路 这些分子可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. In the past, our lab has mostly focused on the molecular control of neuronal responses to injury, and in particular axon regeneration and sprouting following CNS 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, we have 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 proposal, we will comprehensively investigate the neuron and astrocyte specific roles of LZK and DLK in the multicellular response to spinal cord injury using an array of inducible loss and gain of function mouse genetic lines. Downstream effectors of DLK and LZK will be identified through transcriptomic analyses in neurons and astrocytes. Functional synergies or redundancies will be tested between DLK and LZK, and the interaction with other signaling pathways including Stat3 and Pten will be tested as well. Together, these studies will determine the contribution of DLK and LZK in axonal repair and astrocyte response after spinal cord injury, which may pave the way for therapeutic development targeting these molecules to promote repair and recovery after spinal cord injury.