Sphingosine-1-phosphate system as a therapeutic target for amyotrophic lateral sclerosis

1-磷酸鞘氨醇系统作为肌萎缩侧索硬化症的治疗靶点

• 批准号: 10476986
• 负责人: ALPASLAN DEDEOGLU
• 金额: --
• 依托单位: VA BOSTON HEALTH CARE SYSTEM
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2025-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10476986
• 关键词: ALS patients; Affect; Age; Alzheimer' s disease model; Amyloid beta-Protein; Amyotrophic Lateral Sclerosis; Anatomy; Animal Model; Anti-Inflammatory Agents; Antiinflammatory Effect; Apoptosis; Area; Astrocytes; Atrophic; Autopsy; Biochemical; Blood - brain barrier anatomy; Body Weight; Brain; Ceramides; Cerebral cortex; Cessation of life; Clinical; Clinical assessments; Complex; Data; Diagnosis; Diffusion; Disease; Disease Progression; Dose; Etiology; FOXP3 gene; Functional disorder; Gene Mutation; Generations; Genes; Goals; Human; Imaging Techniques; Immune system; Immunosuppressive Agents; Infiltration; Inflammation; Lipids; Longevity; Lumbar spinal cord structure; Lymphocyte; Lymphocyte Activation; Lymphocyte Depletion; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Memory; Metabolism; Microglia; Monitor; Motor; Motor Cortex; Motor Neurons; Multiple Sclerosis; Mus; Muscle Weakness; Natural Immunity; Nature; Neuraxis; Neuroglia; Onset of illness; Oral; Paralysed; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Pharmacology; Phase; Phenotype; Phosphotransferases; Process; Recovery; Regulatory T-Lymphocyte; Role; Sampling; Signal Transduction; Specificity; Spectrum Analysis; Sphingolipids; Sphingosine; Sphingosine-1-Phosphate Receptor; Spinal Cord; Survival Rate; Symptoms; System; T-Lymphocyte; Techniques; Testing; Therapeutic; Tissues; Transgenic Organisms; Translating; Tumor-infiltrating immune cells; amyotrophic lateral sclerosis therapy; analog; appropriate dose; biobank; blood-brain barrier crossing; cytokine; early onset; effective therapy; gray matter; improved; lipid metabolism; migration; motor neuron degeneration; mouse model; multiple sclerosis treatment; nervous system disorder; neurochemistry; neuroinflammation; neurotoxic; neurotrophic factor; novel strategies; novel therapeutic intervention; novel therapeutics; oligodendrocyte progenitor; optimal treatments; preclinical study; prevent; protein TDP-43; receptor; remyelination; research clinical testing; response; side effect; spasticity; sphingosine 1-phosphate; sphingosine-1-phosphate lyase; sphingosine-1-phosphate phosphatase; stem cells; superoxide dismutase 1; therapeutic target; translational study; treatment effect; white matter

Amyotrophic lateral sclerosis (ALS) is a progressive, fatal, and untreatable neurological disease characterized by muscle weakness, atrophy and spasticity, typically leading to paralysis and death within 3-5 years after symptom onset. Pathologically, ALS is primarily characterized by the degeneration and death of motor neurons (MN) in the cerebral cortex and spinal cord. Damage to MN is associated with the onset of ALS however the progressive loss of motor neurons is a non-cell autonomous process that requires damage of neighboring non- neuronal cells. Indeed, the presence of reactive astrocytes and microglia in heavily-affected areas is a hallmark of ALS. Deregulation of lipid metabolism and malfunction of the immune system have been implicated in the pathogenesis of ALS. Sphingolipid metabolism was identified as the most dysregulated pathway, and ceramide species, which promote apoptosis and inflammation, were found to accumulate in postmortem spinal cord samples of ALS patients. Influx of T lymphocytes into the central nervous system occur early in the disease. While some lymphocytes activate neuroinflammation others, regulatory T cells (Tregs), hold neuroinflammation in check. Protective and harmful phenotypes of microglia and astrocytes appear to coexist in affected tissue. The fact that immunosuppressant treatments have been disappointing in ALS may be because of the dual nature of the immune system. Fingolimod is a structural analog of sphingosine that has been approved for the oral treatment of multiple sclerosis. Unlike conventional immunosuppressive drugs, fingolimod does not inhibit lymphocyte activation but reduces the migration of pathogenic lymphocytes into the central nervous system (CNS) and increases the number of circulating Tregs. Fingolimod readily crosses the blood brain barrier and in the CNS, promotes the neuroprotective phenotype in glial cells. In a recent preclinical study, fingolimod improved the survival rate of SOD1-G93A mice, a mouse model of ALS, and the beneficial effect was associated with modulation of microglial activation and innate immunity. We propose a study to test the hypothesize that altered the S1P signaling drives the proinflammatory activation of astrocytes and microglia in ALS and that treatment with S1P modulators will interfere with the proinflammatory process to slow down (or recover) the degeneration of MN with the ultimate goal of paving the way to find new therapies to treat or cure the disease. In Aim 1 we will use two different mouse models of ALS (SOD1-G93A and TDP43-Q331K) and human postmortem lumbar cord samples from ALS patients to investigate the S1P system in the etiology ALS to establish the rational for using modulators of the S1P signaling system for the treatment of ALS. In Aim 2 we will perform a dose-response study (1, 0.3, 0.1, and 0.03 mg/kg/day) starting at a pre- or post-onset stage using fingolimod that acts on S1P1,3,4,5 and AUY954, a second generation S1P modulators with specificity to S1P1. In Aim 3 we will determine anatomical differences in the spinal cord of treated and untreated ALS mice using ex-vivo magnetic resonance (MR) imaging, a technique with high potential to translate to humans. The study incorporates principles of rational pharmacology and clinical evaluation combined with state-of-the-art neuropathological, neurochemical, and MR spectroscopy and imaging techniques to define the therapeutic benefits of S1P modulators and will provide valuable data towards understanding the pathological process of ALS and finding new approaches to treat, diagnose, and monitor the disease.

肌萎缩侧索硬化症(ALS)是一种进行性、致命性和不可治疗的神经系统疾病。 由于肌肉无力、萎缩和痉挛，通常会在3-5年后导致瘫痪和死亡 症状出现。病理上，肌萎缩侧索硬化症的主要特征是运动神经元的变性和死亡。 (Mn)在大脑皮层和脊髓中。MN的损害与ALS的发病有关，但 运动神经元的进行性丢失是一个非细胞的自主过程，需要邻近的非 神经细胞。事实上，重灾区反应性星形胶质细胞和小胶质细胞的存在是一个标志。 肌萎缩侧索硬化症。脂代谢的失调和免疫系统的功能障碍被认为与 ALS的发病机制。鞘磷脂代谢被认为是最不平衡的途径，神经酰胺 促进细胞凋亡和炎症的物种被发现在死后的脊髓中积聚 ALS患者的样本。T淋巴细胞进入中枢神经系统的现象发生在疾病的早期。 一些淋巴细胞激活神经炎症，而另一些则是调节性T细胞(Tregs)，控制神经炎症 在检查中。保护性和有害表型的小胶质细胞和星形胶质细胞似乎在病变组织中共存。 免疫抑制治疗在ALS中一直令人失望的事实可能是因为两面性 对免疫系统的影响。Fingolimod是一种鞘氨醇的结构类似物，已被批准用于口服 治疗多发性硬化症。与传统的免疫抑制药物不同，Fingolimod不抑制 淋巴细胞活化，但减少致病淋巴细胞向中枢神经系统的迁移 (CNS)，并增加循环Tregs的数量。Fingolimod可以轻松地穿过血脑屏障，进入 中枢神经系统，促进神经胶质细胞的神经保护表型。在最近的一项临床前研究中，Fingolimod改善了 对ALS小鼠模型SOD1-G93A小鼠的存活率和有益作用与 小胶质细胞活化和先天免疫的调节。我们提出了一项研究，以检验改变了的假设 S1P信号驱动ALS中星形胶质细胞和小胶质细胞的促炎活化及其治疗 S1P调节剂将干扰促炎症过程，以减缓(或恢复)变性 最终目标是为找到治疗或治愈这种疾病的新疗法铺平道路。在目标1中，我们将 使用两种不同的ALS小鼠模型(SOD1-G93A和TDP43-Q331K)和人死后腰髓 从ALS患者样本中调查S1P系统在ALS发病机制中的作用，为其合理使用奠定基础 治疗肌萎缩侧索硬化症的S1P信号系统调制器。在目标2中，我们将进行剂量反应 研究(1、0.3、0.1和0.03毫克/公斤/天)，从发病前或发病后阶段开始，使用作用于 S1P1、3、4、5和AUY954是S1P1特异性的第二代S1P调节剂。在《目标3》中，我们将 用体外磁学方法确定治疗前后ALS小鼠脊髓的解剖学差异 磁共振(MR)成像，一种具有很大潜力移植到人类身上的技术。这项研究纳入了 合理的药理学和临床评价原则结合最新的神经病理学， 神经化学、磁共振波谱和成像技术，以确定S1P的治疗益处 并将为了解ALS的病理过程和发现 治疗、诊断和监测这种疾病的新方法。