Mechanisms of Oligodendrocyte and Axonal Abnormalities After Perinatal Brain Injury

围产期脑损伤后少突胶质细胞和轴突异常的机制

• 批准号: 9639038
• 负责人: Vittorio Gallo
• 金额: $ 44.63万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-30 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9639038
• 关键词: AMPA Receptors; Ablation; Action Potentials; Affect; Animal Model; Axon; Behavioral; Biochemical; Birth trauma; Brain Injuries; Cell Lineage; Cell Maturation; Cells; Cerebral Palsy; Child; Chronic; Cognitive; Complex; Corpus Callosum; Data; Defect; Development; Diffuse; Doctor of Philosophy; Down-Regulation; Electron Microscopy; Electrophysiology (science); Exposure to; Frequencies; Functional disorder; Future; Glutamates; HIF1A gene; Histone Deacetylase; Hypoxia; Injury; Lead; Learning Disabilities; Light; Mediating; Mediator of activation protein; Molecular; Molecular Target; Motor; Myelin; Neonatal; Neuroglia; Neurologic; Neurons; Nodal; Oligodendroglia; Pathology; Pathway interactions; Perinatal Brain Injury; Phosphorylation; Physiological; Play; Premature Birth; Premature Infant; Property; Recovery; Regulation; Role; SIRT1 gene; Structure; Survivors; Synapses; Testing; Therapeutic Intervention; adverse outcome; base; cellular targeting; disability; genetic manipulation; hippocampal pyramidal neuron; insight; loss of function; lung injury; myelination; neurobehavioral; novel therapeutic intervention; oligodendrocyte lineage; oligodendrocyte progenitor; overexpression; postsynaptic; premature; presynaptic; prevent; progenitor; programs; protein expression; white matter injury

A major cause of chronic disability in survivors of premature birth is diffuse white matter injury (DWMI) and hypomyelination. Altered development of the WM is directly associated with adverse outcomes, including cerebral palsy, cognitive delay and neurobehavioral problems. The cellular pathophysiology underlying DWMI and abnormal myelination is complex and not fully understood. WM glia, and particularly oligodendrocytes (OLs) and their progenitors (OPCs), are susceptible to injury that often occurs in premature birth. We have previously used an animal model of hypoxia (HX)-induced global WMI to demonstrate that OPCs display delayed maturation, which results in abnormal myelination and altered WM function. We have uncovered major aspects of the cellular dysmaturation pathology underlying HX-induced delayed myelination in corpus callosum, including enhanced OPC proliferation associated with decreased OL differentiation, and disrupted myelin ultrastructure. Our recent analysis of OL development in corpus callosum (CC) demonstrates that: i) the prolonged proliferative state of OPCs and delayed OL differentiation in HX is a result of changes in HIF1α- dependent expression and activity of the histone deacetylases Sirt1 and Sirt2, respectively; ii) HX reduces synaptic glutamate (Glu) release from cortical pyramidal neurons on OPCs, which normally downregulates OPC proliferation, and iii) HX compromises axonal integrity and function in SCWM, resulting in altered axon/myelin interactions. Based on these results, we now propose to test the hypothesis that HX-induced protracted WM immaturity arises from intrinsic (Sirt1 and Sirt2) and extrinsic (synaptic) dysregulation of OPC proliferation and OL maturation, thus affecting axonal integrity and function. Firstly, we will establish the role of Sirt2 as a crucial mediator of HX-induced delayed OL maturation in CC. Secondly, we will define the role of non-cell autonomous, glutamate-mediated synaptic changes in regulating OPC proliferation and delayed OL maturation in CC after HX. Finally, we will define the effects of HX and the role of delayed OL maturation on axonal integrity/function in CC. Together, these studies will not only shed light on crucial cellular mechanisms of HX-induced delay in WM maturation, but might also lead to the development of new therapeutic approaches aimed at lessening the long-term neurological sequelae of premature birth.

早产生存期慢性残疾的主要原因是弥漫性白质损伤（DWMI）和 低切率。 WM的开发改变与不良结果直接相关，包括 脑瘫，认知延迟和神经行为问题。 DWMI的细胞病理生理学 异常的髓鞘形成很复杂，不完全理解。 WM神经胶质，尤其是少突胶质细胞 （OLS）及其祖细胞（OPC）容易受到过早出生时经常发生的伤害。我们有 先前使用了缺氧动物模型（HX）诱导的全局WMI来证明OPC显示 延迟成熟，导致髓鞘异常和WM功能改变。我们发现了专业 细胞不饱和病理的各个方面HX引起的延迟髓鞘形式 callosum，包括与OL分化减少相关的增强的OPC增殖，并破坏 髓鞘超微结构。我们最近对call体开发（CC）的OL开发的分析表明：i） OPC的长时间增殖状态和HX中OL分化的延迟是HIF1α-的变化的结果 组蛋白脱乙酰基酶SIRT1和SIRT2的依赖表达和活性； ii）HX减少 从OPC上的皮质金字塔神经元释放突触谷氨酸（GLU），该神经元通常下调 OPC增殖，iii）HX损害了SCWM中的轴突完整性和功能，从而改变了 轴突/髓磷脂相互作用。基于这些结果，我们现在建议测试HX诱导的假设 长期的WM不成熟是由OPC的内在（SIRT1和SIRT2）和外部（突触）失调产生的 增殖和OL成熟，从而影响轴突完整性和功能。首先，我们将确定 SIRT2是CC中HX诱导的延迟OL成熟的关键介质。其次，我们将定义 在调节OPC增殖和延迟OL时，非电池自主，谷氨酸介导的突触变化 HX后CC成熟。最后，我们将定义HX的影响和延迟OL成熟对 CC中的轴突完整性/功能。总之，这些研究不仅会阐明关键的细胞机制 HX引起的WM成熟延迟，但也可能导致新的治疗方法的发展 旨在减轻早产的长期神经后遗症。