Pathological Mechanotransduction by Oligodendrocytes After Traumatic Brain Injury

项目总结 创伤性脑损伤(TBI)是美国认知和运动障碍的主要原因， 估计会导致约1%至2%的人口长期残疾。目前，所有 侧重于限制脑外伤后神经退行性变的药物治疗在 预防继发性后遗症。因此，预防继发性认知和运动后遗症是一种 神经科学研究中尚未得到满足的重大需求。 白质内的长髓鞘轴突容易受到身体创伤和这些神经束的破坏 脑外伤导致白质萎缩，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，对动作电位的强健繁殖和 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 轴突的易损性增加，使其易于退化。虽然是渐进性和慢性的白色 颅脑损伤后物质异常的报道，其机制是由机械应变对脑组织启动的 导致少突胶质细胞功能障碍和白质丢失的定义仍然不明确。我的初步数据显示 多因素脑损伤导致少突胶质细胞谱系发生动态变化。使用公开可用的RNA 测序数据I表明，YAP可以转录激活基因 脑创伤后少突胶质细胞前体细胞(OPC)表达上调。YAP及其共转录激活子PDZ- 结合基序(TAZ)是河马信号通路的核效应器，是一种高度保守的通路， 调节器官的生长和再生。已知少突胶质细胞和OPC对机械刺激有反应 如剪切力等刺激通过YAP的作用，然而YAP过度活动在这方面的后果 血统尚不清楚。我证明YAP过度活跃足以损害OPC的分化。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 OPC和2)YAP是否保持OPC中的祖先状态并解锁神秘的转录程序 当过度激活时。这些目标将使用干细胞生物学和基因组学相结合的方法来实现 技术，与体内疾病建模相结合。了解YAP的功能后果 少突胶质细胞谱系的活跃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。

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.