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: 10314368
• 负责人: Erin Frances Cohn
• 金额: $ 4.6万
• 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/10314368
• 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; 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; Lead; Ligands; Maintenance; Mechanics; Mediating; Mediator of activation protein; Molecular; Motor; Myelin; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Neuroglia; Neurologic; Neurons; Neurosciences Research; Nuclear; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Pharmacology; Phosphotransferases; Play; Population; Prevention; Process; Proteins; Reporting; Role; Secondary Prevention; Signal Pathway; Signal Transduction; Signal Transduction Pathway; Stimulus; Techniques; Technology; Therapeutic; Transcription Coactivator; Transcriptional Regulation; Trauma; Traumatic Brain Injury; United States; biological adaptation to stress; brain tissue; cellular development; chromatin protein; disability; extracellular; fluid percussion injury; genome-wide; in vivo; in vivo Model; insight; knock-down; mechanical force; mechanotransduction; motor disorder; motor impairment; nervous system disorder; neuroprotection; neurotransmission; notch protein; novel therapeutics; oligodendrocyte lineage; oligodendrocyte progenitor; organ growth; organ regeneration; 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.

项目摘要 创伤性脑损伤（TBI）是美国认知和运动障碍的主要原因， 估计会导致大约1%至2%的人口长期残疾。目前所有 专注于限制TBI后神经退行性变的药物治疗在 防止继发性后遗症。因此，预防继发性认知和运动后遗症是 神经科学研究中未满足的重要需求。 白色物质中的长的有髓鞘轴突在损伤后容易受到物理创伤和这些神经束的破坏。 TBI导致白色物质萎缩，这与认知和运动功能障碍密切相关。髓鞘 是由成熟的少突胶质细胞产生的，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 增加轴突的脆弱性，使其易于退化。虽然进行性和慢性白色 据报道，脑外伤后出现了物质异常，这种机制是由脑组织上的机械应变引起的， 导致少突胶质细胞功能障碍和白色物质损失仍然不清楚。我的初步数据显示 多因素脑外伤诱导少突胶质细胞谱系的动态变化。用公开的RNA 测序数据表明，Yes相关蛋白（雅普）可以转录激活基因 在TBI后少突胶质祖细胞（OPC）中上调。雅普及其共转录激活因子PDZ- 结合基序（TAZ）是Hippo信号通路的核效应子，Hippo信号通路是一种高度保守的通路， 调节器官生长和再生。已知少突胶质细胞和OPCs响应于机械刺激。 刺激，如剪切应力通过行动的雅普，然而，后果的雅普过度活跃，在这 血统不明。我证明，雅普过度活跃是足以损害OPC分化。目标 将试图定义1）雅普活性的调节如何影响细胞的分化和增殖， OPCs和2）雅普是否保持OPCs的祖细胞状态并解锁一个隐藏的转录程序 会变得异常活跃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，结合体内疾病建模。了解雅普的功能后果 少突胶质细胞谱系的活性将为预防或逆转神经系统后遗症提供新的机会。 影响数百万美国人的脑外伤