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、致命性和不可治愈的神经系统疾病，其特征在于 肌肉无力，萎缩和痉挛，通常导致瘫痪和死亡后3-5年内 症状发作。在病理学上，ALS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的损伤与ALS的发作有关， 运动神经元的进行性丧失是一种非细胞自主过程， 神经元细胞事实上，在严重受影响的区域存在反应性星形胶质细胞和小胶质细胞是一个标志， 的ALS。脂质代谢的失调和免疫系统的功能障碍已经被牵连在这些疾病中。 ALS的发病机制。鞘脂代谢被确定为最失调的途径，神经酰胺 在死后脊髓中发现了促进凋亡和炎症的物质 ALS患者的样本。T淋巴细胞流入中枢神经系统发生在疾病的早期。 虽然一些淋巴细胞激活神经炎症，但其他调节性T细胞（TCFs）保持神经炎症 在检查。小胶质细胞和星形胶质细胞的保护和有害表型似乎共存于受影响的组织中。 事实上，免疫抑制剂治疗一直令人失望的ALS可能是因为双重性质， 免疫系统。芬戈莫德是鞘氨醇的结构类似物，其已被批准用于口服给药。 多发性硬化症的治疗与传统的免疫抑制药物不同，芬戈莫德不抑制 淋巴细胞活化，但减少致病性淋巴细胞迁移到中枢神经系统 (CNS)并增加了循环中的T细胞的数量。芬戈莫德容易穿过血脑屏障， CNS促进神经胶质细胞中的神经保护表型。在最近的一项临床前研究中，芬戈莫德改善了 SOD 1-G93 A小鼠（ALS小鼠模型）的存活率和有益效果与 调节小胶质细胞活化和先天免疫。我们提出了一项研究来验证假设， S1 P信号传导驱动ALS中星形胶质细胞和小胶质细胞的促炎性激活， S1 P调节剂将干扰促炎过程，以减缓（或恢复） MN的最终目标是为寻找治疗或治愈这种疾病的新疗法铺平道路。在目标1中， 使用两种不同的ALS小鼠模型（SOD 1-G93 A和TDP 43-Q331 K）和人死后腰髓 从ALS患者中抽取样本，探讨S1 P系统在ALS病因学中的作用，建立其应用的合理性 用于治疗ALS的S1 P信号传导系统的调节剂。在目标2中，我们将进行剂量反应 在发作前或发作后阶段开始使用芬戈莫德的研究（1、0.3、0.1和0.03 mg/kg/天）， S1 P1，3，4，5和AUY 954，对S1 P1具有特异性的第二代S1 P调节剂。在目标3中， 使用离体磁共振成像技术测定经治疗和未经治疗的ALS小鼠的脊髓中的解剖学差异 磁共振（MR）成像，一种具有很高潜力的技术转化为人类。该研究纳入了 合理的药理学和临床评价原则结合最先进的神经病理学， 神经化学、磁共振波谱和成像技术来确定S1 P的治疗益处 调节剂，并将提供有价值的数据，了解ALS的病理过程和发现 治疗、诊断和监测疾病的新方法。