Accelerating remyelination using lanthionine ketimine derivatives

使用羊毛硫氨酸酮亚胺衍生物加速髓鞘再生

• 批准号: 10708047
• 负责人: Douglas L. Feinstein
• 金额: --
• 依托单位: JESSE BROWN VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-10-01 至 2026-09-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10708047
• 关键词: Acceleration; Action Potentials; Address; Adult; Amino Acids; Anxiety; Area; Axon; Behavior; Behavioral; Brain Stem; Calcium; Cell Differentiation process; Cell Maturation; Cell Membrane Permeability; Chemicals; Chronic; Clinical; Confocal Microscopy; Corpus Callosum; Cuprizone; Cyclization; Data; Demyelinating Diseases; Demyelinations; Disease; Disease Progression; Electron Microscopy; Electrophysiology (science); Equilibrium; Esters; Experimental Autoimmune Encephalomyelitis; FDA approved; General Population; Genes; Goals; Healthcare Systems; Image; Immune Targeting; Immune system; In Vitro; Inflammation; Inflammatory; Inflammatory Response; Ion Channel; Ischemia; Knockout Mice; Lead; Lesion; Locomotor Recovery; Lymphocyte; Mediating; Memory; Metabolic; Methods; Modeling; Motor; Multiple Sclerosis; Myelin; Myelin Sheath; N-Methyl-D-Aspartate Receptors; Natural regeneration; Nerve; Neural Conduction; Neurites; Neurodegenerative Disorders; Neuroglia; Neurological outcome; Neurons; Nitric Oxide; Oligodendroglia; Optic Nerve; Parents; Peptides; Peripheral; Permeability; Persons; Pharmaceutical Preparations; Phenotype; Phosphorylation; Prevalence; Production; Property; Quality of life; Ranvier' s Nodes; Rattus; Regenerative capacity; Sensory; Spinal Cord; Spinal cord injury; Spinal nerve structure; Structure; Symptoms; Testing; Thick; Thinness; Veterans; Woman; Work; axon injury; collapsin response mediator protein-2; conditional knockout; dosage; experimental study; fluid percussion injury; functional outcomes; functional restoration; gray matter; improved; in vivo; lanthionine; motor deficit; mouse model; multiple sclerosis patient; multiple sclerosis treatment; nerve injury; neuroprotection; neurotoxicity; novel; object recognition; oligodendrocyte progenitor; oligodendrocyte-myelin glycoprotein; rehabilitative care; remyelinating agent; remyelination; restoration; screening; stem cells; trend; voltage

The major goal of this project is to identify novel compounds which will accelerate remyelination within the CNS of patients with Multiple Sclerosis (MS). While many therapies have been developed to treat MS, almost all target the immune system in efforts to reduce ongoing damage; in contrast relatively few target the regenerative capacity of myelin producing Oligodendrocytes (OLGs) to restore function. In ongoing studies to characterize the beneficial effects of Lanthionine Ketimine Ester (LKE), a semi-synthetic amino acid derivative, we found that LKE not only reduces clinical signs in a mouse model of MS, but also accelerates remyelination following chemically induced, non-inflammatory demyelination by cuprizone (CPZ). In vitro screening of new LKE derivatives suggests some are more potent than the parent compound. This raises the main hypothesis that LKE and new derivatives will increase remyelination and restore functional outcomes. This will be addressed in the following aims: Aim 1: Extend our initial studies of LKE benefit using the CPZ model, including optimization of LKE dosage and duration; and comparisons of LKE following modest (CPZ for 2 weeks) or extensive (CPZ for 5-9 weeks) stages of demyelination. Assessments will include electron and confocal microscopy of myelin, axons, and Nodes of Ranvier; analysis of OPC maturation; neuronal damage; and glial inflammation. Aim 2: Characterize LKE-treatment induced improvement on functional outcomes, including improvement in nerve conductance by recording compound action potentials across the corpus callosum; and behavioral analysis to assess motor and balance improvement with rotarod; novel object recognition to assess memory and anxiety; and y-maze to assess memory. Aim 3: Complete screening of 4 lead LKE-derivatives to identify those having the highest efficacy (lowest dosage, more rapid or robust increase) to induce OPC maturation, best metabolic stability, and highest membrane permeability. The best candidate will be tested in the CPZ model and directly compared to LKE. Aim 4: Use in vivo and in vitro experiments to explore mechanisms of action of LKE and derivatives. This will include electrophysiological methods and calcium imaging to examine effects of LKE on CRMP2, and its interactions with Voltage Gated Ca2+ Channels (VGCCs) in OPCs. Available conditional knockout mice for CRMP2 will allow testing if CRMP2 in OPCs mediates LKE actions.

该项目的主要目标是识别能够加速中枢神经系统内髓鞘再生的新型化合物 多发性硬化症 (MS) 患者。虽然已经开发出许多治疗多发性硬化症的疗法，但几乎所有疗法都针对 免疫系统努力减少持续的损害；相比之下，相对较少的目标是再生 产生髓磷脂的少突胶质细胞（OLG）恢复功能的能力。在正在进行的研究中描述 羊毛硫氨酸酮亚胺酯 (LKE)（一种半合成氨基酸衍生物）的有益作用，我们发现 LKE 不仅可以减轻多发性硬化症小鼠模型的临床症状，还可以加速髓鞘再生 铜宗 (CPZ) 化学诱导的非炎症性脱髓鞘。新LKE的体外筛选 衍生物表明有些比母体化合物更有效。这就提出了 LKE 的主要假设 新的衍生物将增加髓鞘再生并恢复功能结果。这将在 以下目标： 目标 1：使用 CPZ 模型扩展我们对 LKE 益处的初步研究，包括优化 LKE 剂量和 期间;以及中度（CPZ 2 周）或广泛（CPZ 5-9 周）阶段后 LKE 的比较 脱髓鞘。评估将包括髓磷脂、轴突和神经节的电子和共聚焦显微镜检查。 朗维尔； OPC 成熟度分析；神经元损伤；和神经胶质炎症。 目标 2：表征 LKE 治疗引起的功能结果改善，包括功能改善 通过记录胼胝体复合动作电位来测量神经电导；和行为 分析以评估转棒的运动和平衡改善；新颖的物体识别来评估记忆和 焦虑;和 y 迷宫来评估记忆力。 目标 3：全面筛选 4 种主要 LKE 衍生物，以确定具有最高功效的衍生物（最低剂量、 更快速或更强劲的增加）以诱导 OPC 成熟、最佳代谢稳定性和最高的膜 渗透性。最佳候选者将在 CPZ 模型中进行测试，并直接与 LKE 进行比较。 目标 4：利用体内和体外实验探索 LKE 及其衍生物的作用机制。这将 包括电生理方法和钙成像来检查 LKE 对 CRMP2 的影响及其 与 OPC 中电压门控 Ca2+ 通道 (VGCC) 的相互作用。可用的条件敲除小鼠 CRMP2 将允许测试 OPC 中的 CRMP2 是否介导 LKE 操作。