Glial HIFa: mechanisms and implications in hypoxia/ischemia-induced oligodendroglial pathology

神经胶质HIFa：缺氧/缺血诱导的少突胶质细胞病理学的机制和意义

• 批准号: 10581693
• 负责人: Fuzheng Guo
• 金额: $ 47.26万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-05-01 至 2026-02-28
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10581693
• 关键词: Affect; Animal Model; Animals; Astrocytes; Biology; Birth; Brain; Brain Hypoxia-Ischemia; Cell Differentiation process; Cells; Central Nervous System; Clinical; Clinical Research; Communication; Data; Development; Diffuse; Diffuse Axonal Injury; Diffusion; Environment; Exposure to; Felis catus; Future; Genetic; Gestational Age; Goals; HIF1A gene; Human; Hypoxia; Hypoxia Inducible Factor; Impairment; In Vitro; Infant; Knowledge; Lesion; Mediating; Mediator; Molecular; Mus; Myelin; Nature; Neuroglia; Oligodendroglia; Pathologic; Pathology; Pathway interactions; Periventricular Leukomalacia; Physiological; Pregnancy; Premature Birth; Premature Infant; Public Health; Regulation; Reporting; Respiratory System; Role; Seminal; Survivors; System; Testing; Textbooks; Therapeutic; Therapeutic Intervention; Time; United States; Virulence Factors; Visit; WNT Signaling Pathway; autocrine; beta catenin; design; effective therapy; glial activation; glial cell development; in vivo; innovation; insight; ischemic injury; motor deficit; mouse model; mutant; myelination; neurodevelopment; novel; oligodendrocyte progenitor; paracrine; premature; stem cells; tool; white matter; white matter injury

Glial HIFa: mechanisms and implications in hypoxia/ischemia-induced oligodendroglial pathology Preterm birth before 37th gestational week affects 1 of 10 infants and is an enormous burden on public health. Due to the immaturity of the respiratory system and the brain white matter vasculature of preterm infants, hypoxia/ischemia (H/I)-elicited diffuse white matter injury (WMI) frequently occurs in preterm brain. Disturbed myelination is a hallmark pathological feature in diffuse WMI. Impaired differentiation of myelin-producing oligodendrocytes from oligodendrocyte progenitor cells (referred to as OPC differentiation) is a primary culprit for disturbed myelination. No clinical therapies exist for promoting myelination in preterm infants affected by WMI. Therefore, studying molecular mechanisms underlying arrested OPC differentiation in WMI is important and instrumental in designing myelination therapies for treating hypomyelination in preterm infants. This project aims to define molecular mechanisms underlying the disturbed myelin formation in diffuse WMI with a focus on the function and mechanisms of glial HIFα in OPC differentiation and myelination. The developing central nervous system (CNS) is exposed to a physiologically hypoxic environment under which hypoxia inducible factor alpha, HIFα (HIF1α and HIF2α) is transiently stabilized to regulate neural development. The role of HIFα in glial cell development remains unknown until a seminal study reported a concept that oligodendroglial HIFα stabilization disturbed normal OPC differentiation through activating autocrine Wnt signaling (Yuen et al., 2014 Cell). However, our recent in vivo study (Zhang et al., 2020 Nature Communications) weakens the concept and unraveled a glial type-specific HIFα-Wnt regulation: oligodendroglial HIFα does not regulate Wnt signaling while astroglial HIFα surprisingly does. Our submitted study (Zhang et al., 2020 BioRxiv, doi:10.1101/2020.03.30.015131) further demonstrated an autocrine Wnt-independent role of HIFα in normal oligodendroglial development and discovered a novel HIFα target whose activation inhibits OPC differentiation. Going forward to WMI, we found persistent HIFα activation in glial cells and interestingly, dampening such HIFα activation mitigated myelination disturbance in an animal model for diffuse WMI. Built on these substantive data, we propose an overarching hypothesis that, under WMI, oligodendroglial HIFα regulates OPC differentiation in a manner independent of autocrine Wnt signaling as previously thought (tested in Aim 1), instead, through activating SOX9, a new non-canonical HIFα target we identified (tested in Aim 2) and that astrocytes control OPC differentiation through HIFα-activated paracrine Wnt signaling (tested in Aim 3). We will use glial type-specific and time-conditional genetic mutants and a preterm human brain-equivalent mouse model for diffuse WMI to test our hypothesis. This project will likely advance our fundamental mechanism knowledge of glial HIFα in oligodendroglial biology and pathology and provide new data into the therapeutic potential of glial HIFα in overcoming disturbed myelination in preterm infants affected by diffused WMI.

Glial HIFA：缺氧/缺血引起的寡头病理学的机理和含义 第37周之前的早产会影响10个婴儿中的1个，并且是公共卫生的巨大伯宁。 由于早产儿的呼吸系统和脑白质脉管系统的不成熟， 低氧/缺血（H/I）引起的弥漫性白质损伤（WMI）经常发生在早产大脑中。不安 髓鞘化是弥漫性WMI中的标志性病理特征。产生髓磷脂的分化受损 来自少突胶质细胞祖细胞的少突胶质细胞（称为OPC分化）是主要的罪魁祸首 为了扰乱的髓鞘。没有临床疗法来促进受婴儿的髓鞘形成 WMI。因此，研究WMI中逮捕的OPC分化的分子机制很重要 并有助于设计髓鞘化疗法，以治疗早产儿中的髓样疗法。这个项目 旨在定义弥漫性WMI中受影响的髓磷脂形成的基础的分子机制，重点是 神经胶质HIFα在OPC分化和髓鞘中的功能和机制。发展中心 神经系统（CNS）暴露于身体缺氧的环境中，在该环境下诱发缺氧 因子α，HIFα（HIF1α和HIF2α）瞬时稳定以调节神经发育。 HIFα的作用 在神经胶质细胞的发育中，直到第二次研究报告了一个寡头HIFα的概念 稳定通过激活自分泌Wnt信号传导扰乱了正常OPC的分化（Yuen等，2014 细胞）。但是，我们最近的体内研究（Zhang等人，2020年自然通讯）削弱了概念和 解开神经胶质型特异性HIFα-WNT调节：寡头HIFα不调节Wnt信号传导 而星形胶质HIFα令人惊讶地做到了。我们提交的研究（Zhang等，2020 Biorxiv， doi：10.1101/2020.03.30.015131）进一步证明了HIFα在正常中的无自分泌Wnt的作用 少突齿发育，发现了一个新型的HIFα靶标，其激活抑制了OPC分化。 到了WMI，我们发现神经胶质细胞中的HIFα激活持续，有趣的是，使这种情况发生了 HIFα激活减轻了弥漫性WMI动物模型中的髓鞘灾难。建立在这些上 实质性数据，我们提出了一个总体假设，在WMI下，寡头HIFα会调节 OPC以独立于自分泌Wnt信号传导独立的方式分化（在AIM 1中进行了测试）， 取而代 星形胶质细胞通过HIFα激活的旁分泌Wnt信号传导控制OPC分化（在AIM 3中进行了测试）。我们将 使用神经胶质类型特异性和时间条件的遗传突变体和早产的人类脑等效小鼠 弥漫性WMI检验我们的假设的模型。这个项目可能会推动我们的基本机制 在寡头生物学和病理学中了解神经胶质HIFα的知识，并将新数据提供给治疗 神经胶质HIFα在克服受弥漫性WMI影响的早产婴儿中的骨髓性扰动的潜力。