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.

早产幸存者慢性残疾的一个主要原因是弥漫性白色物质损伤（DWMI）， 髓鞘形成不足WM的改变与不良结局直接相关，包括 大脑性麻痹、认知延迟和神经行为问题。DWMI的细胞病理生理学基础 并且异常髓鞘形成是复杂的并且未被完全理解。WM胶质细胞，特别是少突胶质细胞 (OLs)和它们的祖细胞（OPCs）容易受到早产中经常发生的损伤。我们有 先前使用缺氧（HX）诱导的动物模型来证明OPCs显示 延迟成熟，导致髓鞘形成异常和WM功能改变。我们发现少校 HX诱导的体部髓鞘形成延迟的细胞发育不良病理学方面 胼胝体，包括与OL分化降低相关的OPC增殖增强， 髓鞘超微结构我们最近对胼胝体（CC）中OL发育的分析表明：i） HX中OPCs的增殖状态延长和OL分化延迟是HIF 1 α- 分别依赖于组蛋白脱乙酰酶Sirt 1和Sirt 2的表达和活性; ii）HX降低 突触谷氨酸（Glu）释放从皮质锥体神经元上的OPC，这通常下调 iii）HX损害SCWM中的轴突完整性和功能，导致改变的 轴突/髓鞘相互作用。基于这些结果，我们现在提出测试假设，HX诱导 持续的WM不成熟是由OPC的内在（Sirt 1和Sirt 2）和外在（突触）失调引起的 增殖和OL成熟，从而影响轴突的完整性和功能。首先，我们将确立 Sirt 2是CC中HX诱导的OL成熟延迟的关键介质。其次，我们将确定 非细胞自主的，谷氨酸介导的突触变化调节OPC增殖和延迟OL HX后在CC中成熟。最后，我们将定义HX的影响以及OL成熟延迟对 CC中的轴突完整性/功能。总之，这些研究不仅将揭示关键的细胞机制， HX诱导的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。