Stimulating oligodendrocyte progenitor cell differentiation and remyelination

刺激少突胶质细胞祖细胞分化和髓鞘再生

• 批准号: 8792420
• 负责人: Seema K Tiwari-Woodruff
• 金额: $ 33.25万
• 依托单位: UNIVERSITY OF CALIFORNIA RIVERSIDE
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-02-01 至 2018-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8792420
• 关键词: Action Potentials; Adverse effects; Agonist; Alanine Transaminase; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Astrocytes; Axon; Biological; Biological Markers; Brain; Breast; Cell Differentiation process; Cell Proliferation; Cell Survival; Chemicals; Chloride Ion; Chlorides; Chronic; Clinical; Collaborations; Corpus Callosum; Cuprizone; Data; Demyelinating Diseases; Demyelinations; Development; Development Plans; Diet; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dose; Drug Exposure; Electron Microscopy; Estradiol; Estrogen Receptors; Excretory function; Exhibits; Experimental Autoimmune Encephalomyelitis; Follicle Stimulating Hormone; Generic Drugs; Genes; Gliosis; Goals; Growth Factor; Health; Human; Human Development; Image; Imaging Device; Indazoles; Inflammatory; Investigational Drugs; Knock-out; Ligands; Link; Luteinizing Hormone; Mediating; Metabolism; Microglia; Mission; Modeling; Motor; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Nerve Degeneration; Nervous System Physiology; Neuraxis; Neurological outcome; Neurons; Oligodendroglia; Onset of illness; Optic Nerve; Optic Neuritis; Optical Coherence Tomography; Outcome; Pathogenesis; Pathology; Pathway interactions; Patients; Performance; Pharmaceutical Preparations; Proteins; Proteolipids; Public Health; Regimen; Research; Rodent Model; Role; Safety; Second Messenger Systems; Serum; Signal Transduction; Signal Transduction Pathway; Specificity; Spinal Cord; Splenocyte; Stem cells; Therapeutic; Therapeutic Agents; Tissues; Translating; Treatment Efficacy; Visual evoked cortical potential; absorption; axonal degeneration; axonopathy; cell type; cellular targeting; clinical application; clinical efficacy; cytokine; diarylpropionitrile; disability; dosage; enhanced green fluorescent protein; human FRAP1 protein; improved; in vivo; innovation; interest; mouse model; myelination; nerve stem cell; nervous system disorder; neuroimaging; neuron loss; neuroprotection; novel strategies; oligodendrocyte-myelin glycoprotein; pre-clinical; preclinical evaluation; prevent; propionitrile; remyelination; reproductive; safety study; second messenger; subventricular zone

DESCRIPTION (provided by applicant): Currently available immunomodulatory therapies do not modulate the pathogenesis of axonal degeneration once it is established and are only partially effective in preventing the onset of permanent disability in MS patients. Identifying a drug that stimulates endogenous myelination and spares axon degeneration would theoretically reduce the rate of disease progression. We have previously shown that treatment of demyelinating mouse models with estrogen receptor (ER)b ligand; diarylpropionitrile (DPN) has the potential for fulfilling this role. Because DPN is a generic ERb ligand with low specificity we screened higher specificity ERb and found that Indazole-Cl was the best ERb ligand. The objective is to achieve in vivo proof of principle in multiple sclerosis (MS) animal models to establish feasibility of the development candidate Indazole-Cl for MS treatment. Using the optimal dosing regimen, a direct effect of Indazole-Cl on stimulation of endogenous oligodendrocyte (OL) progenitor cell (OPC) survival and differentiation, axon remyelination, and neuroprotection is expected. Mechanisms of action will be investigated via second messenger signaling and target cell type. Translationally-relevant imaging will be used to visualize effects n a chronic MS mouse model. Moreover, assessment of Indazole-Cl-induced changes in serum cytokine and growth factors will be assessed to confirm potential biomarkers and clinical application. Eventually, safety studies to support pre-clinical candidate nomination and dossier completion will be performed. The proposed research is inspired by Indazole-Cl's strong dossier and encouraging preliminary results demonstrating its therapeutic efficacy in a chronic MS mouse model. Specifically, stimulation of endogenous remyelination and improved axon function and neurological outcomes were observed and appear mediated by increased resident OPC survival and differentiation. Quiescent OPCs exist in MS lesions and are not effectively activated by largely immunomodulatory current MS drugs. We aim to target endogenous OPCs using Indazole-Cl, thereby developing MS treatment that slows disease progression with intermittent, short-term dosing regimens.

描述(由申请人提供)：目前可用的免疫调节疗法一旦确定轴突变性就不能调节其发病机制，在防止MS患者发生永久性残疾方面只有部分有效。从理论上讲，找到一种能刺激内源性髓鞘形成并避免轴突变性的药物将会降低疾病的进展速度。我们之前已经证明，用雌激素受体(ER)b配体；二芳基丙腈(DPN)治疗脱髓鞘小鼠模型具有实现这一作用的潜力。因为DPn是一种特异性较低的普通ERb配体 筛选出特异性较高的Erb，发现吲哚氯是最佳的Erb配基。目的是在多发性硬化症(MS)动物模型中实现体内原理验证，以确定开发用于MS治疗的候选药物吲唑-氯的可行性。在最佳给药方案下，吲唑氯有望直接刺激内源性少突胶质细胞(OL)祖细胞(OPC)存活和分化、轴突再髓鞘形成和神经保护。作用机制将通过第二信使信号和靶细胞类型进行研究。翻译相关的成像将用于可视化慢性多发性硬化症小鼠模型的效果。此外，将评估吲唑氯诱导的血清细胞因子和生长因子的变化，以确认潜在的生物标志物和临床应用。最终，将进行安全性研究，以支持临床前候选人提名和档案完成。这项拟议的研究的灵感来自于吲唑-氯的强大卷宗和令人鼓舞的初步结果，证明了其在慢性多发性硬化症小鼠模型中的治疗效果。具体地说，观察到内源性重新髓鞘形成的刺激以及轴突功能和神经结果的改善，并似乎通过增加常驻OPC的存活率和分化来调节。静止的OPC存在于MS病变中，并且不能被目前主要的免疫调节药物有效地激活。我们的目标是使用吲达唑-氯来靶向内源性OPC，从而开发出通过间歇、短期给药方案来减缓疾病进展的MS治疗方法。