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: 10664897
• 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/10664897
• 关键词: ALS patients; Activated Lymphocyte; 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; Body Weight; Brain; Cell physiology; Central Nervous System; Ceramides; Cerebral cortex; Cessation of life; Clinical; Clinical assessments; Complex; Cortical Cord; 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; Inflammatory; 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; Neuroglia; Onset of illness; Oral; Paralysed; Pathogenesis; Pathogenicity; Pathologic; Pathologic Processes; Pathology; Pathway interactions; Pharmaceutical Preparations; 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; amyotrophic lateral sclerosis therapy; analog; biobank; blood-brain barrier crossing; cytokine; effective therapy; glial activation; gray matter; immune cell infiltrate; improved; lipid metabolism; migration; motor neuron degeneration; mouse model; multiple sclerosis treatment; nervous system disorder; neurochemistry; neuroinflammation; neuropathology; neuroprotection; 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、致命性且无法治愈的神经系统疾病 由于肌肉无力、萎缩和痉挛，通常会在术后 3-5 年内导致瘫痪和死亡 症状发作。病理上，ALS的主要特征是运动神经元的变性和死亡 (MN) 位于大脑皮层和脊髓。 MN 的损伤与 ALS 的发生有关，但是 运动神经元的进行性丧失是一个非细胞自主过程，需要损害邻近的非细胞 神经元细胞。事实上，受影响严重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 肌萎缩侧索硬化症。脂质代谢失调和免疫系统功能障碍与 ALS 的发病机制。鞘脂代谢被认为是最失调的途径，而神经酰胺 促进细胞凋亡和炎症的物种被发现在死后脊髓中积累 ALS 患者样本。 T 淋巴细胞流入中枢神经系统发生在疾病早期。 虽然一些淋巴细胞会激活神经炎症，但另一些淋巴细胞，即调节性 T 细胞 (Treg)，则会抑制神经炎症 检查中。小胶质细胞和星形胶质细胞的保护性和有害表型似乎在受影响的组织中共存。 免疫抑制剂治疗 ALS 的效果令人失望，这可能是由于其双重性 免疫系统的。芬戈莫德是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，芬戈莫德不会抑制 淋巴细胞活化，但减少致病淋巴细胞迁移至中枢神经系统 (CNS) 并增加循环 Tregs 的数量。芬戈莫德很容易穿过血脑屏障， 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，芬戈莫德改善了 SOD1-G93A 小鼠（ALS 小鼠模型）的存活率，其有益效果与 小胶质细胞激活和先天免疫的调节。我们提出一项研究来测试改变的假设 S1P 信号传导驱动 ALS 中星形胶质细胞和小胶质细胞的促炎激活，并且该治疗 使用 S1P 调节剂会干扰促炎过程，从而减缓（或恢复）退化 MN 的最终目标是为寻找治疗或治愈该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）和人类死后腰椎 来自 ALS 患者的样本，调查 ALS 病因中的 S​​1P 系统，以确定使用 S1P 系统的合理性 用于治疗 ALS 的 S1P 信号系统调节剂。在目标 2 中，我们将执行剂量反应 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是针对S1P1的第二代S1P调制器。在目标 3 中，我们将 使用离体磁力确定治疗和未治疗的 ALS 小鼠脊髓的解剖学差异 磁共振（MR）成像，一种很有可能转化为人类的技术。该研究包括 合理药理学和临床评估的原则与最先进的神经病理学相结合， 神经化学、磁共振波谱和成像技术来确定 S1P 的治疗益处 调节剂，将为理解 ALS 的病理过程和寻找发现提供有价值的数据 治疗、诊断和监测该疾病的新方法。