Oligodendroglial Intrinsic Ring Finger Protein family members are injury specific, but not developmental, regulators of oligodendrocyte maturation

少突胶质细胞固有环指蛋白家族成员是损伤特异性的，但不是发育性的少突胶质细胞成熟的调节因子

• 批准号: 10239257
• 负责人: Stephen Philip James Fancy
• 金额: $ 20.19万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10239257
• 关键词: Adult; Axon; Biology; Cell surface; Cerebral Palsy; Development; Disease; Disease Progression; Exposure to; FZD1 gene; Failure; Family member; Genes; Grant; Human; Injury; Intrinsic factor; Kinetics; Knockout Mice; Lesion; Ligands; LoxP-flanked allele; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Myelin Sheath; Natural regeneration; Neurologic Dysfunctions; Oligodendroglia; Process; Protein Family; Proteins; Regenerative response; Regulation; Ring Finger Domain; Signal Transduction; Surface; Therapeutic Intervention; Tissues; WNT Signaling Pathway; Zinc Fingers; beta catenin; body system; cognitive disability; in vivo; injury and repair; intestinal epithelium; myelination; newborn brain injury; oligodendrocyte lineage; oligodendrocyte precursor; programs; receptor; recruit; remyelination; repaired; small molecule; small molecule inhibitor; targeted treatment; ubiquitin-protein ligase; white matter; white matter injury

PROJECT ABSTRACT: Permanent damage to white matter tracts, comprising axons and myelinating oligodendrocytes (OL), is an important component of Multiple Sclerosis (MS) in adults, as well as brain injuries of the newborn that cause cerebral palsy and cognitive disabilities. However, regulatory factors relevant in human developmental myelin disorders and in myelin regeneration are unclear. In both conditions, damaged myelin sheaths can be regenerated by oligodendrocyte precursors (OPCs) that are recruited to lesions and differentiate in a process called remyelination. But this myelin regenerative response often fails [1, 2], and contributes significantly to ongoing neurological dysfunction, axonal loss and disease progression, and it is critical to understand mechanisms underlying this failure of endogenous injury repair in humans. Much has been learnt about the regulation of oligodendrocyte biology in remyelination from the study of development, and indeed the recapitulation hypothesis of myelin regeneration proposes that mechanisms that underlie remyelination after injury are essentially a rerunning of a developmental myelination program [3]. However, human myelin repair is highly susceptible to failure, despite the robustness of developmental myelination, suggesting key differences in the regulation of the two processes. Little is understood about whether there are oligodendroglial intrinsic factors that operate specifically in the setting of injury but not in development, and how these might become dysregulated. Here we identify oligodendroglial intrinsic Ring Finger Protein family members as injury specific regulators of oligodendrocyte maturation kinetics, that do not function in development but are critical for remyelination, uncovering key regulatory differences between the OL intrinsic program of developmental myelination and regeneration. In this grant, we will 1) identify the functions of Ring Finger Family members RNF43 (Ring Finger Protein 43) and ZNRF3 (Zinc and Ring Finger 3) in development and injury in OL lineage, showing that they function to regulate OPC maturation kinetics only in the setting of injury, 2) identify how they are regulated in OL lineage, and demonstrate that RNF43 is a marker that identifies activated OPCs responding to injury in human MS lesions, 3) identify their function to repress Wnt signaling via regulation of surface presentation of specific Frizzled receptor family members on OPCs, and that small molecule manipulation of a Frizzled signaling axis can be used to promote myelin regeneration.

项目摘要： 对白质区的永久损害，包括轴突和髓鞘的少突胶质细胞（OL）是 成人多发性硬化症（MS）的重要组成部分，以及新生儿的脑损伤 脑瘫和认知障碍。但是，与人类发育性髓鞘相关的监管因素 疾病和髓鞘再生尚不清楚。在这两种情况下，受损的髓鞘可能是 由少突胶质细胞前体（OPC）再生，这些前体（OPC）被募集到病变并在过程中分化 称为再髓。但是这种髓磷脂再生反应通常会失败[1，2]，并为 持续的神经功能障碍，轴突丧失和疾病进展，了解 人类内源性损伤修复失败的基础机制。关于 从发展研究中调节少突胶质细胞生物学在remer髓中的调节，实际上是 髓磷脂再生的概括假设提出了基于再生的机制 受伤本质上是发育性髓鞘化计划的重新研究[3]。但是，人髓磷脂修复是 尽管发育性髓鞘形成强大，但极易受到失败的影响，这表明 这两个过程的调节。关于是否存在寡头固有的知识很少 专门在伤害设置但不在发展中的因素，以及这些因素如何 变得失调。在这里，我们将寡头固有的环形手指蛋白家族成员视为损伤 少突胶质细胞成熟动力学的特定调节剂，这些动力学在发育中起作用，但对 再髓，揭示了OL内在发展计划之间的关键调节差异 髓鞘和再生。在这笔赠款中，我们将1）确定无指家族成员的功能 RNF43（环手指蛋白43）和ZnRF3（锌和无名指3）在OL谱系中发育和损伤， 表明它们仅在受伤的情况下才能调节OPC成熟动力学，2）确定它们如何 在OL血统中受到调节，并证明RNF43是标志着激活的OPC响应的标记 要在人类MS病变中受伤，3）确定其功能以通过调节表面抑制Wnt信号传导 在OPC上呈现特定的卷曲受体家族成员，以及对A的小分子操纵 卷曲的信号轴可用于促进髓磷脂再生。