Discovering new therapies to promote myelin repair

发现促进髓磷脂修复的新疗法

• 批准号: 10314338
• 负责人: Alban P Gaultier
• 金额: $ 44万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-08-01 至 2024-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10314338
• 关键词: Adrenergic Antagonists; Affect; Agonist; Algorithms; Animal Model; Antidepressive Agents; Antihistamines; Area; Autoimmune Diseases; Automobile Driving; Axon; Biological; Biology; Blood - brain barrier anatomy; Cell Differentiation process; Cells; Cellular biology; Chemicals; Chemistry; Clinical; Complement; Computers; Data; Demyelinations; Disease; Drug Kinetics; Experimental Autoimmune Encephalomyelitis; FDA approved; Gene Expression Profiling; Goals; Gold; HTR2A gene; Histamine H1 Receptors; Immune; Immune response; Immunosuppressive Agents; Impairment; In Vitro; Inflammatory; Inflammatory Response; Invaded; Investigation; Left; Light; Lipids; Microglia; Monitor; Multiple Sclerosis; Myelin; Myelin Sheath; Nerve; Nerve Degeneration; Neuraxis; Neurobiology; Neurons; Oligodendroglia; Outcome; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacologic Substance; Phase; Pluripotent Stem Cells; Population; Process; Property; Proteins; Proteomics; Quality of life; Reactive Oxygen Species; Regulation; Selective Serotonin Reuptake Inhibitor; Serotonin; Serotonin Agonists; Small Interfering RNA; Stress; Structure; Structure-Activity Relationship; Symptoms; Testing; Therapeutic; Therapeutic Agents; Trazodone; Work; base; brain parenchyma; chronic demyelination; curative treatments; disabling symptom; improved; in silico; in vitro Assay; innovation; macrophage; mouse model; multiple sclerosis patient; multiple sclerosis treatment; myelination; neuron loss; neuroprotection; neurotransmission; novel; novel therapeutics; oligodendrocyte precursor; pharmacophore; precursor cell; prevent; receptor; recruit; remyelination; repaired; success; targeted agent; therapeutic development; tool

Abstract: Multiple sclerosis (MS) is a neurodegenerative, autoimmune disease characterized by the destruction of the neuron-surrounding myelin sheath. Myelin has the double duty of assisting with the propagation of nerve impulses and shielding neurons from external harm. Once immune cells strip the neuron of myelin, exposed axons begin to decay, leading to the debilitating symptoms of MS. Currently approved therapies for MS are aimed at inhibiting the immune response and do not address the need to promote myelin repair. Development of therapeutics that would activate myelination and prevent the irreversible changes associated with neuronal death is paramount to improving the quality of life and survival of MS patients. The central nervous system (CNS) contains oligodendrocyte precursor cells (OPCs) that have the potential to differentiate into mature oligodendrocytes and remyelinate denuded axons, a process that is affected in MS patients. Our long-term goal is to develop new MS treatments that halts neurodegeneration by promoting myelin repair, affording a potentially curative drug. The innovation driving this proposal is an in silico screen that allowed discovery of a molecule that drives OPC differentiation in vitro. The efficacy of this compound was validated in a mouse model of experimental autoimmune encephalomyelitis (EAE, an animal model of MS). Our goal in this proposal is to shed light on the novel mechanism of action of this agent and identify chemotypes that activate remyelination. Guided by strong preliminary evidence, this goal will be achieved by pursuing two specific aims: 1) discover the receptor/protein target of this agent, which is key to OPCs differentiation, and 2) develop our hit compound into drug-like molecules with efficacy and potency suitable for testing in animal models of MS. Our approach is significant because it will lead to identification of protein targets in MS that promote myelination and new therapeutics with novel modes of action. Our investigations will lead to fundamental advances in understanding the regulation of myelination.

摘要： 多发性硬化症（MS）是一种神经退行性自身免疫性疾病，其特征在于 神经元周围的髓鞘。髓磷脂具有协助神经传播的双重功能 脉冲和保护神经元免受外部伤害。一旦免疫细胞剥去神经元的髓鞘， 轴突开始衰退，导致MS的衰弱症状。 其目的在于抑制免疫应答，而没有解决促进髓磷脂修复的需要。发展 激活髓鞘形成并防止与神经元相关的不可逆变化的治疗方法 死亡对于改善MS患者的生活质量和存活率是至关重要的。中枢神经系统（CNS） 含有少突胶质细胞前体细胞（OPCs），具有分化为成熟的 少突胶质细胞和髓鞘再生剥脱的轴突，这一过程在MS患者中受到影响。我们的长期目标 是开发新的MS治疗方法，通过促进髓鞘修复来阻止神经变性， 治疗药物。推动这一提议的创新是一种计算机屏幕，它允许发现一种分子 在体外驱动OPC分化。该化合物的功效在以下小鼠模型中得到验证： 实验性自身免疫性脑脊髓炎（EAE，MS的动物模型）。我们在这个提案中的目标是 阐明这种药物的新作用机制，并确定激活髓鞘再生的化学型。指导 通过强有力的初步证据，这一目标将通过追求两个具体目标来实现：1）发现 受体/蛋白质靶点，这是OPCs分化的关键，和2）将我们的命中化合物开发成 具有适用于MS动物模型测试的功效和效力的药物样分子。我们的方法是 重要的是，它将导致识别MS中促进髓鞘形成的蛋白质靶点， 具有新的作用模式的治疗剂。我们的研究将导致我们对 髓鞘形成的调节。