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

基本信息

批准号：
10705261
负责人：
Vittorio Gallo
金额：
$ 45.5万
依托单位：
CHILDREN'S RESEARCH INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-30 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10705261
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 Learning Disabilities Mediating Mediator Molecular Molecular Target Motor Myelin Neonatal Neuroglia Neurologic Neurons Nodal Oligodendroglia Pathology Pathway interactions Perinatal Brain Injury Phosphorylation Physiological Play Predisposition Premature Birth Premature Infant Proliferating Property Recovery Regulation Role SIRT1 gene Structure Survivors Synapses Testing Therapeutic Intervention adverse outcome cellular targeting cyclin-dependent kinase inhibitor 1B disability gain of function genetic manipulation hippocampal pyramidal neuron insight loss of function lung injury myelination neurobehavioral normoxia novel therapeutic intervention oligodendrocyte lineage oligodendrocyte progenitor overexpression postsynaptic premature presynaptic prevent progenitor programs protein expression white matter injury

项目摘要

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脑白质损伤（DWMI）和 WM 发育的改变与不良后果直接相关，包括脑瘫、认知延迟和神经行为问题 DWMI 的细胞病理生理学。髓鞘形成异常是复杂的，目前尚未完全了解 WM 神经胶质细胞，特别是少突胶质细胞。 (OL) 及其祖细胞 (OPC) 很容易受到早产时经常发生的损伤。先前使用缺氧 (HX) 诱导的整体 WMI 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。 HX 诱导的体内髓鞘形成延迟的细胞发育不良病理学的各个方面胼胝体，包括与 OL 分化减少相关的 OPC 增殖增强，以及破坏我们最近对胼胝体 (CC) OL 发育的分析表明： i) HX 中 OPC 增殖状态延长和 OL 分化延迟是 HIF1α 变化的结果 ii) 组蛋白脱乙酰酶 Sirt1 和 Sirt2 分别依赖于 HX 的表达和活性； OPC 上的皮质锥体神经元释放突触谷氨酸 (Glu)，通常会下调 OPC 增殖，以及 iii) HX 损害 SCWM 中的轴突完整性和功能，导致改变基于这些结果，我们现在建议检验 HX 诱导的假设。长期 WM 不成熟是由 OPC 的内在（Sirt1 和 Sirt2）和外在（突触）失调引起的增殖和 OL 成熟，从而影响轴突完整性和功能。首先，我们将确定 OL 的作用。 Sirt2 作为 CC 中 HX 诱导的 OL 成熟延迟的关键介质。非细胞自主、谷氨酸介导的突触变化调节 OPC 增殖和延迟 OL 最后，我们将定义 HX 的影响以及延迟 OL 成熟的作用。总之，这些研究不仅将揭示关键的细胞机制。 HX 引起的 WM 成熟延迟，但也可能导致新治疗方法的开发旨在减少早产的长期神经系统后遗症。