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.

项目摘要 大脑通过多种神经元与脊髓进行交流，共同称为 脊柱上连接。脊柱上的连接组具有广泛的电动机，感官和自主神经。 功能，以及脊髓损伤（SCI）对下降区域的损害，因此导致了广泛的功能 挑战：损失精细的运动控制，移动和平衡的丧失，感觉丧失，神经性疼痛， 膀胱，肠，温度和血压失调，性功能的丧失等等。寻址 这些无数的功能缺陷将需要详细了解潜在的细胞复杂性。这里， 使用鼠标模型，我们将利用单个测序技术的进步，并结合 我们实验室最近制定的条形码策略，以全面介绍基因转录的模式 这代表了各种类别的脊柱上神经元。然后，我们将挑战脊柱损伤的神经元 并监视基因表达逐个人群的基因表达的变化，从而获得了有史以来的首先见解 整个脊柱上连接组的细胞损伤反应的共同点和差异。最后，我们 将使用Sox11处理多种脊柱上细胞类型，Sox11是一种转录因子，已被证明可变促进 轴突修复或触发不同细胞类型的细胞死亡，并介绍其特定人群的作用。合并，这个 工作将产生对基线分子类型的基线分子差异的新见解，提供新颖的标记 基因简化细胞细胞类型的分析，并揭示对损伤天生敏感的种群 和/或尝试干预。