Pathological Mechanotransduction by Oligodendrocytes After Traumatic Brain Injury

脑外伤后少突胶质细胞的病理性机械转导

• 批准号: 10685379
• 负责人: Erin Frances Cohn
• 金额: $ 2.62万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-09-01 至 2024-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10685379
• 关键词: Action Potentials; Affect; American; Atrophic; Axon; Binding; Binding Proteins; Binding Sites; Biochemical; Biology; Cell Differentiation process; Cell Line; Cell Nucleus; Cell physiology; Cells; Central Nervous System; Cessation of life; ChIP-seq; Chemicals; Chronic; Clustered Regularly Interspaced Short Palindromic Repeats; Cognitive; Complex; Coupling; Cues; Cytoplasm; Data; Demyelinations; Development; Diagnosis; Disease; Disease model; Dominant Genes; Enhancers; Environment; Functional disorder; Gene Expression; Genes; Genetic; Genetic Transcription; Genomics; Health; Hyperactivity; Immunohistochemistry; Impaired cognition; Impairment; In Vitro; Injury; Interruption; Knock-out; LATS1 gene; Ligands; Maintenance; Mechanics; Mediating; Mediator; Molecular; Motor; Myelin; Nerve Degeneration; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurosciences Research; Nuclear; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Phosphorylation; Phosphotransferases; Play; Population; Prevention; Process; Proliferating; Protein Microchips; Proteins; Reporting; Role; Secondary Prevention; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Techniques; Technology; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Trauma; Traumatic Brain Injury; United States; biological adaptation to stress; brain tissue; cellular development; disability; extracellular; fluid percussion injury; genome-wide; in vivo; in vivo Model; insight; knock-down; mechanical force; mechanical stimulus; mechanotransduction; motor disorder; motor impairment; nervous system disorder; neuroprotection; neurotransmission; notch protein; novel therapeutics; oligodendrocyte lineage; oligodendrocyte progenitor; organ growth; organ regeneration; pharmacologic; preservation; prevent; progenitor; programs; promoter; protein expression; receptor; response; shear stress; small molecule inhibitor; stem cell biology; stem cell function; stem cell proliferation; stem cells; tool; transcription factor; transcriptome sequencing; white matter

PROJECT SUMMARY Traumatic brain injury (TBI) is a leading cause of cognitive and motor impairment in the United States and is estimated to result in long-term disability in approximately 1 to 2 percent of the population. Currently, all pharmacological therapies focused on limiting neurodegeneration after TBI have been unsuccessful in preventing secondary sequelae. Therefore, the prevention of secondary cognitive and motor sequelae is a significant unmet need in neuroscience research. Long myelinated axons within white matter are vulnerable to physical trauma and disruption of these tracts after TBI results in white matter atrophy that is strongly correlated with both cognitive and motor dysfunction. Myelin is generated by mature oligodendrocytes and is essential for robust propagation of action potentials and for the survival and integrity of neuronal axons. Oligodendrocyte death and demyelination can therefore result in increased vulnerability of axons, predisposing them to degeneration. Although progressive and chronic white matter abnormalities are reported after TBI, the mechanisms initiated by mechanical strain on brain tissue that contribute to oligodendrocyte dysfunction and white matter loss remain poorly defined. My preliminary data show that multifactorial TBI induces dynamic changes in the oligodendrocyte lineage. With publicly available RNA sequencing data I demonstrate that Yes-associated protein (YAP) may transcriptionally activate genes upregulated in oligodendrocyte progenitor cells (OPCs) after TBI. YAP and its co-transcriptional activator PDZ- binding motif (TAZ) are the nuclear effectors of the Hippo signaling pathway, a highly conserved pathway that regulates organ growth and regeneration. Oligodendrocytes and OPCs are known to respond to mechanical stimuli such as shear stress through the actions of YAP, however the consequences of YAP hyperactivity in this lineage are unknown. I demonstrate that YAP hyperactivity is sufficient to impair OPC differentiation. The aims of this proposal will seek to define 1) how modulation of YAP activity affects differentiation and proliferation of OPCs and 2) whether YAP maintains the progenitor state in OPCs and unlocks a cryptic transcriptional program when hyperactivated. These aims will be achieved using a combination stem cell biology and genomics techniques, in conjunction with in vivo disease modeling. Understanding the functional consequences of YAP activity in the oligodendrocyte lineage will offer new opportunities to prevent or reverse the neurological sequalae of traumatic brain injury that affect millions of Americans.

项目概要 创伤性脑损伤 (TBI) 是美国认知和运动障碍的主要原因，并且 据估计，大约 1% 至 2% 的人口会出现长期残疾。目前，所有 专注于限制 TBI 后神经退行性变的药物治疗在 防止继发后遗症。因此，预防继发性认知和运动后遗症是一个重要的任务。 神经科学研究中存在重大未满足的需求。 白质内的长有髓轴突很容易受到身体创伤和这些束的破坏 TBI 导致白质萎缩，与认知和运动功能障碍密切相关。髓磷脂 由成熟的少突胶质细胞产生，对于动作电位的稳健传播和 神经元轴突的存活和完整性。因此，少突胶质细胞死亡和脱髓鞘可导致 轴突的脆弱性增加，使其易于退化。尽管进行性和慢性白斑 TBI 后报告物质异常，这是由脑组织机械应变引发的机制， 导致少突胶质细胞功能障碍和白质损失的因素仍不清楚。我的初步数据显示 多因素 TBI 会引起少突胶质细胞谱系的动态变化。具有公开的 RNA 测序数据证明 Yes 相关蛋白 (YAP) 可能转录激活基因 TBI 后少突胶质细胞祖细胞 (OPC) 上调。 YAP 及其共转录激活剂 PDZ- 结合基序 (TAZ) 是 Hippo 信号通路的核效应器，这是一条高度保守的通路， 调节器官生长和再生。已知少突胶质细胞和 OPC 对机械反应有反应 通过 YAP 的作用产生剪切应力等刺激，但是 YAP 过度活跃的后果 血统不明。我证明 YAP 过度活跃足以损害 OPC 分化。目标 该提案将寻求定义 1) YAP 活性的调节如何影响细胞的分化和增殖 OPCs 和 2) YAP 是否维持 OPCs 中的祖细胞状态并解锁神秘的转录程序 当过度活跃时。这些目标将通过干细胞生物学和基因组学的结合来实现 技术，与体内疾病模型相结合。了解 YAP 的功能后果 少突胶质细胞谱系的活动将为预防或逆转神经后遗症提供新的机会 影响数百万美国人的创伤性脑损伤。