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.

肌萎缩性侧索硬化症（ALS）是一种进行性，致命和不可治疗的神经系统疾病的特征 由于肌肉无力，萎缩和痉挛，通常在3 - 5年内导致瘫痪和死亡 症状发作。从病理上讲，ALS主要以运动神经元的变性和死亡为特征 （MN）在大脑皮层和脊髓中。 MN的损害与ALS的发作有关 运动神经元的进行性丧失是一个非电池自主过程，需要损害相邻的非 - 神经元细胞。实际上，受影响的地区的反应性星形胶质细胞和小胶质细胞的存在是一个标志 ALS。免疫系统的脂质代谢和故障的放松管制已与 ALS的发病机理。鞘脂代谢被确定为最失调的途径和神经酰胺 发现促进凋亡和炎症的物种积聚在​​验尸脊髓中 ALS患者的样本。 T淋巴细胞流入中枢神经系统的早期。 一些淋巴细胞激活神经炎症其他，而调节性T细胞（TREG）持有神经炎症 在检查中。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。 免疫抑制治疗在ALS中令人失望的事实可能是因为双重性质 免疫系统。 fingolimod是已批准口头的鞘氨醇的结构类似物 多发性硬化症的治疗。与常规的免疫抑制药物不同，芬诺莫德不抑制 淋巴细胞激活，但减少了致病性淋巴细胞向中枢神经系统的迁移 （CNS）并增加了循环Treg的数量。芬洛莫德很容易越过血脑屏障 中枢神经系统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，Fingolimod改进了 SOD1-G93A小鼠的存活率，ALS的小鼠模型以及有益效果与 小胶质激活和先天免疫的调节。我们提出了一项研究，以测试改变的假设 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，该处理 使用S1P调节器将干扰促进过程，以减慢（或恢复）变性 MN的最终目标是为寻找治疗或治愈疾病的新疗法铺平道路。在目标1中，我们将 使用两种不同的鼠标模型的ALS（SOD1-G93A和TDP43-Q331K）和人类术后腰椎绳 来自ALS患者的样本研究病因学中的S1P系统，以建立使用的理性 用于治疗ALS的S1P信号系统的调节器。在AIM 2中，我们将执行剂量反应 研究（1、0.3、0.1和0.03 mg/kg/day）在发作前或发表后阶段，使用作用于fingolimod S1P1,3,4,5和AUY954，是对S1P1的特异性的第二代S1P调节器。在目标3中，我们将 使用EX-VIVO磁 共鸣（MR）成像，这是一种具有很高潜力转化为人类的技术。该研究合并 理性药理学和临床评估的原则结合了最新的神经病理学， 神经化学和MR光谱和成像技术来定义S1P的治疗益处 调节器，并将提供有价值的数据，以了解ALS的病理过程并找到 治疗，诊断和监测疾病的新方法。