Deciphering the Daam2-VHL signaling axis in oligodendrocyte development and white matter injury

破译少突胶质细胞发育和白质损伤中的 Daam2-VHL 信号轴

基本信息

批准号：
10338107
负责人：
Hyun Kyoung Lee
金额：
$ 34.67万
依托单位：
BAYLOR COLLEGE OF MEDICINE
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：
2019-02-01 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338107
关键词：
Address Biochemical Cell Differentiation process Cell Lineage Cells Complex Coupling Data Defect Degradation Pathway Demyelinations Development Developmental Gene Disease Ectopic Expression Event Exhibits Gene Expression Profiling Generations Genes Genetic Genetic Epistasis Goals Human Hypoxia Hypoxia Pathway Hypoxic Brain Damage Injury Ligase Light Mediating Modeling Morphogenesis Mus Myelin Nerve Degeneration Nervous System Physiology Neuraxis Neuroglia Neuronal Dysfunction Neurons Oligodendroglia Pathway interactions Pattern Play Proteins Regenerative capacity Role Signal Transduction System TRIM Motif Testing Ubiquitin Ubiquitination WNT Signaling Pathway base clinically actionable clinically significant emerging adult glial cell development hypoxia neonatorum loss of function mouse model myelination nerve stem cell nervous system disorder neural circuit novel oligodendrocyte myelination oligodendrocyte progenitor programs protein degradation receptor remyelination repaired screening therapeutic development treatment strategy ubiquitin-protein ligase white matter white matter damage white matter injury

项目摘要

SUMMARY and ABSTRACT Glia comprise approximately 60% of the cellular constituency of central nervous system (CNS), playing diverse roles in the functioning CNS and a host of neurological disorders. Development of glial cell lineages proceeds along a tightly regulated program that involves patterning, generation of diverse cells, differentiation, and myelination. This cascade of developmental events is particularly vulnerable to neonatal hypoxic brain injury, which leads to profound loss of myelinating oligodendrocytes (OLs), extensive white matter damage, culminating in neuronal dysfunction. Despite the robust regenerative capacity of OLs, the underlying mechanisms mediating hypomyelination and the subsequent defects in neural circuits after hypoxic injury remain poorly defined. Moreover, myelination continues throughout early adulthood, which also renders the CNS susceptible to insults causing late-onset neurodegeneration. Therefore, the overarching goal of this application is to define new genes and pathways that drive OL maturation during development and repair, and pinpoint potential targetable pathways for white matter disorders. Previously, we identified Daam2 (Disheveled associated activator of morphogenesis 2) as a pivotal regulator of OL myelination and repair, and recently discovered that Daam2 governs OL differentiation through ubiquitination of the hypoxia regulator VHL (von Hippel-Lindau). Moreover, we discovered that Daam2 is regulated by two E3 ligases, Nedd4 (Neural precursor cell expressed developmentally down-regulated protein 4) and Trim9 (Tripartite Motif Containing 9), which in turn govern VHL ubiquitination and OL differentiation. These observations raise two key questions that we will pursue in this proposal: 1) how does Daam2 modulate VHL-HIF signaling in OLs? and 2) how is the ubiquitin-mediated Daam2 degradation controlled in OLs? By understanding the in-depth mechanisms by which Daam2 operates, we will establish Daam2 inhibition as a clinically significant and actionable strategy for the treatment of white matter injury. To answer these key questions, we will first define the reciprocal relationship between Daam2 and VHL during OL development and white matter injury (Aim 1). These studies will define the Daam2-VHL axis as a pivotal regulator of OL development, while revealing novel connections between Wnt signaling and hypoxic pathway during OL myelination. Next, we will determine Daam2 proteasomal degradation pathways in OLs (Aim 2). Upon completion, these studies will define how Daam2 is regulated by target E3 ligases, and identify Nedd4 and Trim9 as novel regulators of OL myelination. A mechanistic understanding of Daam2-VHL axis function in oligodendrocyte repair after injury will shed light on cellular vulnerability to white matter injury and ultimately point to new venues for therapeutic development to stimulate OL remyelination.

总结和摘要神经胶质细胞约占中枢神经系统 (CNS) 细胞成分的 60%，发挥着多种作用在中枢神经系统功能和许多神经系统疾病中发挥作用。神经胶质细胞谱系的发展取得进展沿着严格调控的程序，涉及图案化、不同细胞的生成、分化和髓鞘形成。这种级联的发育事件特别容易受到新生儿缺氧性脑损伤的影响，这会导致髓鞘少突胶质细胞（OL）的严重丧失、白质的广泛损伤，最终导致神经元功能障碍。尽管 OL 具有强大的再生能力，但其潜在的介导髓鞘形成低下以及缺氧损伤后神经回路缺陷的机制仍然不明确。此外，髓鞘形成持续到成年早期，这也使得中枢神经系统容易受到损伤，导致迟发性神经变性。因此，本次活动的总体目标是应用程序是为了定义在发育和修复过程中驱动 OL 成熟的新基因和途径，以及查明白质疾病的潜在目标途径。之前，我们确定了 Daam2 （形态发生的蓬乱相关激活剂 2）作为 OL 髓鞘形成和修复的关键调节剂，以及最近发现 Daam2 通过缺氧调节因子的泛素化来控制 OL 分化 VHL（冯·希佩尔-林道）。此外，我们发现 Daam2 受两个 E3 连接酶 Nedd4（Neural 前体细胞表达发育下调蛋白 4) 和 Trim9（含有三部分基序） 9)，进而控制 VHL 泛素化和 OL 分化。这些观察提出了两个关键我们将在本提案中探讨的问题：1）Daam2 如何调节 OL 中的 VHL-HIF 信号传导？和 2) OL 中泛素介导的 Daam2 降解是如何控制的？通过深入了解 Daam2 的运作机制，我们将把 Daam2 抑制建立为具有临床意义和治疗白质损伤的可行策略。为了回答这些关键问题，我们首先定义 Daam2 和 VHL 在 OL 发育和白质损伤过程中的相互关系（目标 1）。这些研究将 Daam2-VHL 轴定义为 OL 发育的关键调节因子，同时揭示新的 OL 髓鞘形成过程中 Wnt 信号传导与缺氧途径之间的联系。接下来，我们将确定 OL 中的 Daam2 蛋白酶体降解途径（目标 2）。完成后，这些研究将定义如何 Daam2 受目标 E3 连接酶调节，并将 Nedd4 和 Trim9 确定为 OL 髓鞘形成的新型调节剂。对损伤后少突胶质细胞修复中 Daam2-VHL 轴功能的机制理解将有助于阐明研究细胞对白质损伤的脆弱性，并最终指出治疗开发的新途径刺激 OL 髓鞘再生。