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： 白质束（包括轴突和髓鞘少突胶质细胞 (OL)）的永久性损伤是一种 成人多发性硬化症 (MS) 的重要组成部分，以及导致新生儿脑损伤的原因 脑瘫和认知障碍。然而，与人类发育髓磷脂相关的调节因素 疾病和髓磷脂再生尚不清楚。在这两种情况下，受损的髓鞘都可以 由少突胶质细胞前体 (OPC) 再生，这些前体细胞被招募到病变处并在过程中分化 称为髓鞘再生。但这种髓磷脂再生反应经常失败 [1, 2]，并且对 持续的神经功能障碍、轴突丢失和疾病进展，了解这一点至关重要 人类内源性损伤修复失败的潜在机制。已经了解了很多关于 从发育研究来看少突胶质细胞生物学在髓鞘再生中的调节，实际上 髓鞘再生的重演假说提出了髓鞘再生的机制 损伤本质上是发育性髓鞘形成程序的重新运行[3]。然而，人类髓磷脂修复是 尽管发育中的髓鞘形成具有鲁棒性，但仍极易失败，这表明髓鞘形成的关键差异 两个过程的调节。关于少突胶质细胞是否存在内在的知之甚少 特定于伤害发生但不影响发展的因素，以及这些因素如何可能 变得失调。在这里，我们将少突胶质细胞内在环指蛋白家族成员鉴定为损伤 少突胶质细胞成熟动力学的特定调节因子，在发育中不起作用，但对于发育至关重要 髓鞘再生，揭示 OL 内在发育程序之间的关键监管差异 髓鞘形成和再生。在这笔赠款中，我们将 1) 确定无名指家族成员的功能 RNF43（环指蛋白 43）和 ZNRF3（锌和环指 3）在 OL 谱系的发育和损伤中， 表明它们仅在损伤情况下发挥调节 OPC 成熟动力学的作用，2) 确定它们如何 在 OL 谱系中受到调节，并证明 RNF43 是识别激活的 OPC 响应的标记物 人类多发性硬化症病变损伤，3) 确定其通过调节表面抑制 Wnt 信号传导的功能 OPCs 上特定卷曲受体家族成员的呈现，以及小分子操纵 卷曲信号轴可用于促进髓磷脂再生。