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.

这个项目的主要目标是鉴定新的化合物，这将加速中枢神经系统内的髓鞘再生 多发性硬化症（MS）患者。虽然已经开发了许多治疗MS的疗法，但几乎所有的疗法都靶向MS。 免疫系统的努力，以减少正在进行的损害;相反，相对较少的目标，再生 产生髓鞘的少突胶质细胞（OLG）恢复功能的能力。在正在进行的研究中， 半合成氨基酸衍生物Lanthiflavine酮亚胺酯（LKE）的有益效果，我们发现， LKE不仅减少了MS小鼠模型的临床体征，而且还加速了MS后的髓鞘再生。 化学诱导的，非炎性脱髓鞘铜（CPZ）。新LKE的体外筛选 衍生物表明有些比母体化合物更有效。这就提出了一个主要假设，即LKE 新的衍生物将增加髓鞘再生和恢复功能结果。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 持续时间;以及比较中度（CPZ治疗2周）或广泛（CPZ治疗5-9周）阶段后的LKE 脱髓鞘评估将包括髓鞘、轴突和神经节的电子和共聚焦显微镜检查。 Ranvier; OPC成熟分析;神经元损伤;和神经胶质炎症。 目的2：描述LKE治疗诱导的功能结局改善，包括 通过记录胼胝体上的复合动作电位来测量神经传导; 分析以评估旋转棒的运动和平衡改善;新的物体识别以评估记忆和 焦虑;和y-迷宫来评估记忆。 目的3：完成4种先导LKE衍生物的筛选，以鉴定具有最高功效的那些（最低剂量， 更快速或更稳健的增加），以诱导OPC成熟、最佳代谢稳定性和最高的膜渗透率。 磁导率最佳候选者将在CPZ模型中进行测试，并直接与LKE进行比较。 目的4：通过体内外实验研究LKE及其衍生物的作用机制。这将 包括电生理学方法和钙成像，以检查LKE对CRMP 2影响， 与OPC中的电压门控Ca 2+通道（VGCC）的相互作用。可用的条件性基因敲除小鼠 如果OPC中的CRMP 2介导LKE动作，则CRMP 2将允许测试。