Brain-wide transcriptional profiling after spinal cord injury

脊髓损伤后全脑转录谱分析

基本信息

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
项目类别：
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

项目摘要

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.

项目概要大脑通过一组不同的神经元与脊髓进行通信，这些神经元统称为脊髓上连接体。脊髓上连接体具有广泛的运动、感觉和自主神经功能因此，脊髓损伤 (SCI) 对下行束的损害会导致一系列功能障碍挑战：失去精细运动控制、失去运动和平衡、失去感觉、神经性疼痛、膀胱、肠道、体温和血压失调、性功能丧失等。寻址这些无数的功能缺陷需要详细了解潜在的细胞复杂性。这里，使用小鼠模型，我们将利用单一测序技术的进步，并结合我们实验室最近开发的条形码策略，用于全面分析基因转录模式代表不同类别的脊髓上神经元。然后我们将挑战脊髓损伤的下行神经元并监测逐个人群基因表达的变化，从而首次深入了解脊髓上连接组细胞损伤反应的共性和差异。最后，我们将用 Sox11 治疗多种脊髓上细胞类型，Sox11 是一种转录因子，已被证明可以不同程度地促进轴突修复或触发不同细胞类型的细胞死亡，并分析其群体特异性效应。综合起来，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，并提供新的标记物基因以简化对所研究细胞类型的分析，并揭示对损伤先天敏感的群体和/或尝试干预。