Promoting remyelination in multiple sclerosis by simultaneously modulating myelin debris clearance and myelin lipid synthesis

通过同时调节髓磷脂碎片清除和髓磷脂脂质合成促进多发性硬化症的髓鞘再生

• 批准号: 10621894
• 负责人: Jian Hu
• 金额: $ 43.55万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-04-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10621894
• 关键词: Adult; Affect; Agonist; Bexarotene; Brain; Cells; Central Nervous System; Complex; Demyelinating Diseases; Demyelinations; Disease; Etiology; Exhibits; Fatty Acids; Generations; Genes; Genetic; Genetic Transcription; Goals; High Fat Diet; Homeostasis; Immune system; Impairment; Lesion; Lipids; Microglia; Multiple Sclerosis; Multiple Sclerosis Lesions; Mus; Myelin; Names; Natural regeneration; Oligodendroglia; Pathway interactions; Peroxisome Proliferator-Activated Receptors; Persons; Phagocytes; Phagocytosis; Proteins; RXRA gene; Role; Sampling; System; T-Lymphocyte; Testing; Therapeutic; Time; Transcriptional Regulation; United States; chemokine; clinical practice; comparative; cytokine; experimental study; immunomodulatory therapies; insight; lipid biosynthesis; lipid metabolism; lipidomics; mouse model; multiple sclerosis patient; multiple sclerosis treatment; novel therapeutic intervention; prevent; promoter; recruit; reduce symptoms; remyelination; response; transcriptomics

Summary Statement/Abstract Multiple sclerosis (MS) is the most common demyelinating disease, affecting approximately 400,000 people in the United States and 2.5 million people worldwide. It is not clear what causes MS, but many believe that it is because our own immune system attacks oligodendrocytes that generate myelin. However, the current therapies that dampen our immune system can only relieve the symptoms but not cure the disease itself. Therefore, it is urgent to find novel therapeutic approaches that can cure the disease, for instance by promoting remyelination. The central nervous system has great potential to regenerate oligodendrocytes and remyelinate in response to myelin damage, however the ability of remyelination is greatly diminished in the MS lesions. Two major reasons are known to prevent efficient remyelination in MS lesions: 1) damaged myelin cannot be efficiently cleared, thereby preventing formation of new oligodendrocytes, and 2) newly generated and/or existing oligodendrocytes have lost the ability to form new myelin. We have identified a key regulator – Quaking (protein name: Qki; gene name: Qk) – that is potent to overcome both obstacles. Firstly, we discovered that Qki is a key regulator of phagocytosis of microglia. Depletion of Qki in microglia greatly reduced the phagocytic activity of microglia, which is critical for clearance of myelin debris and consequently remyelination. Secondly, we discovered that Qki is a major regulator of oligodendrocyte differentiation and myelin homeostasis by regulating lipid metabolism of both newly formed oligodendrocytes and existing oligodendrocytes in the demyelinating lesions. Mature myelin has been considered an inert material for decades. However, our study showed that mature myelin is in fact a very dynamic material through exploiting our genetic systems by depleting Qki in mature myelinating oligodendrocytes of adult mice. The comparative lipidomic and transcriptomic analyses identified Qki as an essential factor for myelin lipid biosynthesis by controlling the transcription of the lipid metabolism genes, particularly those for fatty acid desaturation and elongation, via coactivation of the peroxisome proliferator- activated receptor beta (PPARβ)-retinoid X receptor alpha (RXRα) complex. These findings were corroborated by functional rescue experiments with brain penetrant PPARβ/RXRα agonists, KD3010 and bexarotene. We hypothesize that restoring lipid metabolism by activating PPARβ/RXRα/Qki function will help remyelination in MS through two ways: 1) activating microglia’s function to clear myelin debris, consequently promoting oligodendrocyte regeneration, and 2) enhancing lipid generation of existing and newly generated oligodendrocytes. To test this hypothesis, we propose the following three specific aims. To test this hypothesis, we propose the following three specific aims: 1) To investigate the role of Qki/PPARβ in microglial phagocytosis in clearing myelin debris and promoting remyelination, 2) to investigate the role of Qki/PPARβ in myelin lipid metabolism and remyelination, and 3) to elucidate the mechanism by which Qki functions as a coactivator to enhance PPARβ transcription activity in both microglia and oligodendrocytes. Our studies will not only provide insights into the etiological mechanism for MS, but more importantly, help MS patients find a cure through targeting remyelinating pathway.

摘要声明/摘要 多发性硬化症 (MS) 是最常见的脱髓鞘疾病，影响着大约 400,000 人 美国和全世界 250 万人。目前尚不清楚导致多发性硬化症的原因，但许多人认为这是因为 我们自己的免疫系统会攻击产生髓磷脂的少突胶质细胞。然而，目前的疗法抑制 我们的免疫系统只能缓解症状，但不能治愈疾病本身。因此，寻找新颖的 可以治愈该疾病的治疗方法，例如通过促进髓鞘再生。中枢神经 然而，该系统具有再生少突胶质细胞和髓鞘再生以应对髓磷脂损伤的巨大潜力 MS 病变中髓鞘再生的能力大大减弱。已知有两个主要原因阻碍了高效 MS病变中的髓鞘再生：1）受损的髓鞘不能被有效清除，从而阻止新髓鞘的形成 少突胶质细胞，2) 新生成的和/或现有的少突胶质细胞失去了形成新髓磷脂的能力。 我们已经确定了一个关键的调节因子——Quaking（蛋白质名称：Qki；基因名称：Qk）——它能够有效克服这两个问题 障碍。首先，我们发现Qki是小胶质细胞吞噬作用的关键调节因子。小胶质细胞中 Qki 的耗竭 大大降低了小胶质细胞的吞噬活性，这对于清除髓鞘碎片至关重要，因此 髓鞘再生。其次，我们发现Qki是少突胶质细胞分化和髓磷脂的主要调节因子 通过调节新形成的少突胶质细胞和现有少突胶质细胞的脂质代谢来维持体内平衡 脱髓鞘病变。几十年来，成熟的髓磷脂一直被认为是一种惰性物质。然而，我们的研究 研究表明，成熟的髓磷脂实际上是一种非常动态的物质，通过消耗我们的遗传系统 成年小鼠成熟髓鞘少突胶质细胞中的 Qki。比较脂质组学和转录组学分析 通过控制脂质代谢的转录，确定 Qki 是髓磷脂脂质生物合成的重要因子 基因，特别是那些通过过氧化物酶体增殖剂的共激活进行脂肪酸去饱和和延伸的基因 激活受体 β (PPARβ)-类视黄醇 X 受体 α (RXRα) 复合物。这些发现得到了证实 使用脑渗透性 PPARβ/RXRα 激动剂、KD3010 和贝沙罗汀进行功能救援实验。我们 假设通过激活 PPARβ/RXRα/Qki 功能恢复脂质代谢将有助于 MS 的髓鞘再生 通过两种方式：1）激活小胶质细胞清除髓磷脂碎片的功能，从而促进少突胶质细胞 再生，2) 增强现有和新生成的少突胶质细胞的脂质生成。为了测试这个 假设，我们提出以下三个具体目标。为了验证这个假设，我们提出以下三个 具体目的： 1) 研究 Qki/PPARβ 在小胶质细胞吞噬作用中清除髓磷脂碎片和 促进髓鞘再生，2) 研究 Qki/PPARβ 在髓磷脂脂质代谢和髓鞘再生中的作用，以及 3) 阐明Qki作为共激活因子增强PPARβ转录活性的机制 小胶质细胞和少突胶质细胞。我们的研究不仅将提供对病因机制的见解 多发性硬化症，但更重要的是，通过靶向髓鞘再生途径帮助多发性硬化症患者找到治愈方法。