Brain-wide transcriptional profiling after spinal cord injury

项目摘要 大脑通过一组不同的神经元与脊髓通信，这些神经元统称为 脊髓上连接体脊髓上连接体携带着广泛的运动、感觉和自主神经功能， 脊髓损伤（SCI）对下行束的损伤导致了广泛的功能性损伤， 挑战：精细运动控制丧失，运动和平衡丧失，感觉丧失，神经性疼痛， 膀胱，肠道，温度和血压失调，性功能丧失等等。解决 这些无数的功能缺陷将需要对潜在的细胞复杂性的详细理解。在这里， 使用小鼠模型，我们将利用单一测序技术的进步，结合 我们实验室最近开发的条形码策略，以全面分析基因转录模式 代表了不同种类的脊髓上神经元。然后我们将挑战脊髓损伤的下行神经元 并监测由此产生的基因表达的变化，有史以来第一次深入了解 脊髓上连接体细胞损伤反应的共性和差异。最后我们 将用Sox 11治疗不同的脊髓上细胞类型，Sox 11是一种转录因子， 轴突修复或触发不同细胞类型的细胞死亡，并描绘其群体特异性效应。结合起来，这 这项工作将对脊髓上细胞类型的基线分子差异产生新的见解， 基因，以简化对未充分研究的细胞类型的分析，并揭示对损伤天生敏感的群体， 或试图干预。

PROJECT SUMMARY The brain communicates with the spinal cord through a diverse set of neurons, collectively termed the supraspinal connectome. The supraspinal connectome carries a broad range of motor, sensory, and autonomic functions, and damage to descending tracts by spinal cord injury (SCI) thus results in a wide array of functional challenges: loss of fine motor control, loss of locomotion and balance, loss of sensation, neuropathic pain, bladder, bowel, temperature, and blood pressure dysregulation, loss of sexual function, and more. Addressing these myriad functional deficits will require a detailed understanding of the underlying cellular complexity. Here, using a mouse model, we will take advantage of advances in single sequencing technologies, combined with a barcoding strategy recently developed by our lab, to comprehensively profile the patterns of gene transcription that typify diverse classes of supraspinal neurons. We will then challenge descending neurons with spinal injury and monitor the resulting changes in gene expression population-by-population, yielding first-ever insight into commonalities and differences in the cellular damage response across the supraspinal connectome. Finally, we will treat diverse supraspinal cell types with Sox11, a transcription factor that has been shown to variably promote axonal repair or trigger cell death in different cell types, and profile its population-specific effects. Combined, this work will yield new insights into baseline molecular differences in supraspinal cell types, provide novel marker genes to simplify analysis of understudied cell types, and reveal populations that are innately sensitive to injury and/or attempted intervention.