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Mechanism of hypoxia mediated failure of oligodendrocyte generation

缺氧介导少突胶质细胞生成失败的机制

基本信息

批准号：
9760799
负责人：
Kevin Cameron Allan
金额：
$ 4.87万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9760799
关键词：
ASCL2 gene Action Potentials Adult Affect Animal Model Apoptosis Axon BHLH Protein Binding Biological Assay Brain Cell Differentiation process Cell Maintenance Cells Cerebrovascular system ChIP-seq Child Chromatin Chronic Clustered Regularly Interspaced Short Palindromic Repeats Cognitive deficits Communication DNA Binding Data Defect Development Diffuse Disease Down-Regulation E-Box Elements Enhancers Exhibits Failure Family Future Gene Targeting Generations Genes Genetic Techniques Genome Hypoxia Hypoxia Inducible Factor Immunohistochemistry Impaired cognition In Vitro Infant Injury Knock-out Lesion Luciferases Maintenance Mediating Modeling Molecular Genetics Mus Myelin Natural regeneration Neuraxis Neurodevelopmental Deficit Neurodevelopmental Disorder Neurologic Neurons Oligodendroglia Perinatal Care Pluripotent Stem Cells Population Premature Birth Premature Infant Recovery Residual state Role Small Interfering RNA Stem cells Testing Therapeutic Intervention Tissues United States Up-Regulation Western Blotting base blocking factor brain tissue cell type experimental study genetic technology in vitro Model in vivo insight knock-down lung development motor deficit motor disorder mouse model new technology novel oligodendrocyte lineage oligodendrocyte progenitor overexpression premature prevent promoter pup restoration spatiotemporal transcription factor white matter white matter injury

项目摘要

PROJECT SUMMARY Nearly 1 out of every 10 children are born prematurely in the United States and although advancements in perinatal care have resulted in the increased survival of preterm infants, many of these children go on to exhibit neurodevelopmental deficits leading to significant cognitive and motor dysfunction. One of the most common neurologic insults following preterm birth is diffuse white matter injury (DWMI), which is thought to arise from hypoxic injury to the developing brain caused by the immature state of lung development and cerebral vasculature and has no cure. White matter is required for communication within the central nervous system and is primarily composed of myelin, which is a fatty sheath that surrounds neuronal axons to allow efficient action potential propagation. Myelin is generated by mature oligodendrocytes, which arise via differentiation of oligodendrocyte progenitor cells (OPCs). In the context of DWMI, hypoxia leads to apoptosis of cells of the oligodendrocyte lineage followed by proliferation and failure of subsequent oligodendrocyte regeneration from residual OPCs. This deficit in oligodendrocyte generation from OPCs following hypoxia can be abrogated by knocking out hypoxia inducible factors (HIFs), which are DNA-binding transcription factors that accumulate under hypoxia and are rapidly degraded in normoxia, in OPCs. However, the mechanism of how HIFs block oligodendrocyte generation remains elusive. Leveraging our lab’s ability to generate large and pure populations of OPCs, I performed ChIP-seq for HIF1a and H3K27Ac, a marker of active chromatin, in order to determine putative HIF targets across the OPC genome. The top candidate target based on HIF1a binding as well as enrichment of H3K27Ac suggested a transcription factor that has been shown to be important for stem cell maintenance in tissues outside the central nervous system as a target of HIF in OPCs. I demonstrate that overexpression of this transcription factor is sufficient to inhibit differentiation of OPCs to oligodendrocytes and is upregulated following hypoxic injury in a mouse model of DWMI. This proposal seeks to further investigate these findings by 1) utilizing a combination of cellular, molecular and genetic techniques to determine the mechanism by which this transcription factor inhibits OPC differentiation 2) determining whether downregulation of this transcription factor will facilitate recovery of oligodendrocyte formation following hypoxic injury in vitro and 3) characterizing the spatiotemporal dynamics of the upregulation of this transcription factor in vivo using a mouse model of DWMI. The experiments outlined in this proposal will increase our understanding of mechanisms that impede oligodendrocyte generation from OPCs under hypoxic conditions, and will uncover novel avenues for therapeutic intervention for this highly prevalent and debilitating neurodevelopmental condition.

项目总结