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：
10556388
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/10556388
关键词：
Biochemical Cell Lineage Cells Central Nervous System 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 Mediating Modeling Morphogenesis Mus Myelin Nerve Degeneration Nervous System Physiology Neuroglia Neuronal Dysfunction Neurons Oligodendroglia Pathway interactions Pattern Play Predisposition Proteins Regenerative capacity Role Signal Transduction System TRIM Motif Testing Ubiquitin Ubiquitination WNT Signaling Pathway clinically actionable clinically significant emerging adult gain of function 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.

摘要和摘要 GLIA约占中枢神经系统（CNS）细胞选区的60％，玩耍多样在功能性中枢神经系统和许多神经系统疾病中的作用。神经胶质细胞谱系的发展进行沿着涉及图案，生成不同细胞的严格调节程序，分化和髓鞘。一系列发育事件尤其容易受到新生儿低氧脑损伤的影响，导致髓鞘少突胶质细胞（OLS）严重丧失，广泛的白质损害，最终导致神经元功能障碍。尽管OLS具有强大的再生能力低氧损伤后神经回路中介导降压效组的机制和随后的缺陷保持较差。此外，整个成年早期的髓鞘形成还在继续，这也使中枢神经系统易受侮辱，导致晚发神经退行性。因此，这是总体目标应用是定义新的基因和途径，这些基因和途径在开发和维修过程中推动OL成熟，以及查明对白质疾病的潜在目标途径。以前，我们确定了DAAM2 （变形的形态发生2）作为OL髓鞘化和修复的关键调节剂，以及最近发现，DAAM2通过泛素化调节剂来控制OL的分化 VHL（von Hippel-Lindau）。此外，我们发现DAAM2受两个E3连接酶（NEDD4）（神经）调节前体细胞表达了发育下调的蛋白质4）和trim9（包含三方基序 9），这又控制VHL泛素化和差异化。这些观察结果提出了两个关键我们将在此提案中提出的问题：1）DAAM2如何调节OLS中的VHL-HIF信号？和2）泛素介导的DAAM2降解如何在OLS中控制？通过了解深入 DAAM2运行的机制，我们将建立DAAM2抑制作用是一种临床意义，并且可行的白质损伤治疗策略。要回答这些关键问题，我们将首先定义在OL发育和白质损伤期间，DaAM2和VHL之间的相互关系（AIM 1）。这些研究将将DAAM2-VHL轴定义为OL发育的关键调节剂，同时揭示了新型 OL髓样期间Wnt信号传导与低氧途径之间的连接。接下来，我们将确定 OLS中的DAAM2蛋白酶体降解途径（AIM 2）。完成后，这些研究将定义 DAAM2受靶E3连接酶的调节，并将NEDD4和TRIM9识别为OL髓鞘化的新调节剂。受伤后的少突胶质细胞修复中DAAM2-VHL轴功能的机械理解会散发关于细胞对白质损伤的脆弱性，最终指向治疗性开发的新场所刺激Ol rebremerination。