Brain-wide transcriptional profiling after spinal cord injury

脊髓损伤后全脑转录谱分析

• 批准号: 10827193
• 负责人: Murray G Blackmore
• 金额: $ 42.49万
• 依托单位: MARQUETTE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-18 至 2025-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10827193
• 关键词: 3-Dimensional; Address; Affect; Anatomy; Apoptotic; Axon; Axotomy; Bar Codes; Bioinformatics; Biological; Bladder; Blood Pressure; Brain; Cell Death; Cell Nucleus; Cells; Cervical; Cervical spinal cord structure; Cervical spine; Classification; Communication; Complex; Corticospinal Tracts; Data; Data Set; Descending Spinal Cord Tract; Detection; Distal; Equilibrium; Exclusion; Future; Gene Delivery; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Genes; Genetic Transcription; Hand; Hypothalamic structure; Individual; Injury; Interruption; Intervention; Intestines; Label; Libraries; Locomotion; Lumbar spinal cord structure; Microscopy; Midbrain structure; Molecular; Monitor; Motor; Motor Pathways; Neuronal Injury; Neurons; Numbness; Paralysed; Pathologic; Pathway interactions; Pattern; Population; Positioning Attribute; Predisposition; Prosencephalon; RNA; Research; Retinal Ganglion Cells; SOX11 gene; Sampling; Sensory; Sex Functioning; Spinal; Spinal Cord; Spinal Injuries; Spinal cord injury; Surveys; Techniques; Technology; Temperature; Therapeutic Intervention; Tissues; Up-Regulation; Vertebral column; Work; axon growth; axon regeneration; cell injury; cell type; connectome; cost; differential expression; hindbrain; innovation; insight; motor control; mouse model; new technology; novel marker; overexpression; painful neuropathy; regenerative; regenerative treatment; repaired; response; response to injury; single cell sequencing; spasticity; transcription factor

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.

项目总结 大脑通过一组不同的神经元与脊髓进行交流，统称为 棘上连接体。棘上连接体具有广泛的运动、感觉和自主神经。 功能，以及脊髓损伤(SCI)对下行束的损害，从而导致广泛的功能性 挑战：失去精细运动控制，失去运动和平衡，失去知觉，神经性疼痛， 膀胱、肠道、体温和血压失调，性功能丧失，等等。寻址 这些无数的功能缺陷需要对潜在的细胞复杂性有详细的了解。这里, 使用老鼠模型，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，用于全面描述基因转录模式 它们代表了不同类别的棘上神经元。然后我们将挑战脊髓损伤的下行神经元 并逐个种群监测由此产生的基因表达变化，从而首次深入了解 椎管上连接体细胞损伤反应的共性和差异。最后，我们 将用sox11处理不同类型的脊柱上细胞，sox11是一种转录因子，已被证明可不同地促进 轴突修复或触发不同细胞类型的细胞死亡，并描述其群体特有的影响。加在一起，这 这项工作将对脊柱上细胞类型的基线分子差异产生新的见解，提供新的标记 基因，以简化对未被研究的细胞类型的分析，并揭示天生对伤害敏感的群体 和/或企图干预。