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。父母R01的目标是识别神经元(目标1) 和星形细胞(目的2)DLK和LZK在脊髓损伤后轴突和组织修复中的作用。我们已经做出了 在这两方面都取得了实质性进展。这一多样性补充旨在支持研究生从一个 代表不足的背景(一位非裔美国女性)，她在这两个问题上都提出了重要的问题 星形胶质细胞LZK在组织保存和损伤后轴突修复中的直接和间接作用具体来说， 受训人员将使用挫伤模型评估星形细胞LZK在组织保存中的直接作用 以及损伤部位的分辨率以及使用遗传获得和功能丧失分析进行的功能恢复。她 然后将使用RiboTag方法描述星形胶质细胞的转录变化，以发现潜在的 星形胶质细胞中LZK信号的介体。使用刺激皮质脊髓轴突再生的方法， 学员将评估操纵LZK介导的星形胶质细胞反应对轴突修复的影响。她还会 绘制LZK和STAT3在调节星形胶质细胞损伤反应中的上位关系。这 在这个过程中掌握的大量工作和实验技术将推动受训者追求 从事独立的神经科学研究，在未来既有科学价值又有翻译价值。这些 实验补充了父R01中的现有组件，同时保持在 原始应用程序。

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. The goal of the parent R01 was to identify the neuronal (Aim 1) and astrocytic (Aim 2) roles of DLK and LZK in axon and tissue repair after spinal cord injury. We have made substantial progress on both fronts. This diversity supplement aims to support a graduate student from an underrepresented background (an African American woman), who is asking the important questions on both the direct and indirect roles of astrocytic LZK in tissue preservation and axonal repair after injury. Specifically, the trainee will use a contusion injury model to assess the direct role of astrocytic LZK in tissue preservation and injury site resolution along with functional recovery using genetic gain and loss of function analyses. She will then profile the transcriptomic changes in the astrocytes using the RiboTag approach to discover potential mediators of LZK signaling in astrocytes. Using methods to stimulate corticospinal axon regeneration, the trainee will assess the effect of manipulating LZK-mediate astrocyte response on axonal repair. She will also map the epistatic relationship between LZK and STAT3 in regulating the astrocyte response to injury. This body of work along with the experimental techniques mastered in this process will propel the trainee to pursue a career in independent neuroscience research that has both scientific and translational value in future. These experiments complement the existing components in the parent R01 while remaining within the overall goal of the original application.