Discovering new therapies to promote myelin repair

摘要： 多发性硬化症(MS)是一种神经退行性自身免疫性疾病，其特征是 神经元周围的髓鞘。髓鞘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。一旦免疫细胞剥离神经元的髓鞘，暴露在 轴突开始衰退，导致多发性硬化症的衰弱症状。目前批准的治疗多发性硬化症的方法是 旨在抑制免疫反应，并不能解决促进髓鞘修复的需要。发展 将激活髓鞘形成并防止与神经元相关的不可逆转变化的治疗方法 死亡对改善MS患者的生活质量和生存至关重要。中枢神经系统(CNS) 含有具有分化为成熟潜能的少突胶质前体细胞(OPC) 少突胶质细胞和脱去髓鞘的轴突，这一过程在多发性硬化症患者中受到影响。我们的长期目标 是开发新的多发性硬化症治疗方法，通过促进髓鞘修复来阻止神经退行性变，提供潜在的 治愈性药物。推动这一提议的创新是一种硅胶屏幕，它允许发现一种分子 这推动了OPC在体外的分化。该化合物的有效性在小鼠模型上得到了验证。 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摆脱 阐明这种药物的新作用机制，并确定激活再髓鞘形成的化学类型。引导式 根据强有力的初步证据，这一目标将通过追求两个具体目标来实现：1)发现 该试剂的受体/蛋白质靶标，这是OPC分化的关键，2)将我们的Hit化合物开发成 具有疗效和效力的类药物分子，适合在多发性硬化症的动物模型中进行测试。 意义重大，因为它将导致在MS中识别促进髓鞘形成的蛋白质靶点和新的 具有新作用模式的治疗学。我们的调查将从根本上促进对 髓鞘形成的调节。

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.