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: 9208812
• 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 2019-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9208812
• 关键词: 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; Chlorides; Chronic; Clinical; Collaborations; Cuprizone; Data; Demyelinating Diseases; Demyelinations; Development; Development Plans; Diet; Diffusion Magnetic Resonance Imaging; Disease; Disease Progression; Dose; Drug Exposure; Electrophysiology (science); Estrogen Receptor alpha; Estrogen Receptor beta; Exhibits; Experimental Autoimmune Encephalomyelitis; FRAP1 gene; Follicle Stimulating Hormone; Generic Drugs; Genes; Gliosis; Goals; Growth Factor; Human; Image; Imaging Device; Indazoles; Investigational Drugs; Ligands; Link; Luteinizing Hormone; Mediating; Microglia; Mission; Modeling; Motor; Multiple Sclerosis; Multiple Sclerosis Lesions; Myelin; Nerve Degeneration; Neuraxis; Neurologic; Neurological outcome; Neurons; Oligodendroglia; Onset of illness; Optic Nerve; Optic Neuritis; Optical Coherence Tomography; Outcome; Pathogenesis; Pathology; Pathway interactions; Performance; Pharmaceutical Preparations; Pharmacology; 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; United States National Institutes of Health; Visual evoked cortical potential; axonal degeneration; axonopathy; cell type; cellular targeting; clinical application; clinical candidate; clinical development; clinical efficacy; cytokine; diarylpropionitrile; disability; dosage; immunoregulation; improved; in vivo; innovation; interest; mouse model; multiple sclerosis patient; multiple sclerosis treatment; myelination; nervous system disorder; neuroimaging; neuron loss; neuroprotection; novel strategies; oligodendrocyte progenitor; oligodendrocyte-myelin glycoprotein; potential biomarker; pre-clinical; preclinical development; preclinical evaluation; prevent; public health relevance; remyelination; reproductive; safety study

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)ß ligand; diarylpropionitrile (DPN) has the potential for fulfilling this role. Because DPN is a generic ERß ligand with low specificity wescreened higher specificity ERb and found that Indazole-Cl was the best ERß 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（由申请方提供）：目前可用的免疫调节疗法一旦确立，就不能调节轴突变性的发病机制，并且在预防MS患者发生永久性残疾方面仅部分有效。确定一种刺激内源性髓鞘形成和避免轴突变性的药物，理论上可以降低疾病进展的速度。我们先前已经证明，用雌激素受体治疗脱髓鞘小鼠模型， (ER)二芳基丙腈（DPN）具有实现这一作用的潜力。由于DPN是一种特异性较低的ERb配体，因此我们筛选了特异性较高的ERb，并发现吲唑-Cl是最好的ERb配体。目的是在多发性硬化（MS）动物模型中实现原理的体内验证，以确定开发候选药物吲唑-Cl治疗MS的可行性。使用最佳给药方案，预期吲唑-Cl对刺激内源性少突胶质细胞（OL）祖细胞（OPC）存活和分化、轴突髓鞘再生和神经保护的直接作用。将通过第二信使信号传导和靶细胞类型来研究作用机制。将使用平移相关成像来可视化慢性MS小鼠模型中的效应。此外，将评估吲唑-Cl诱导的血清细胞因子和生长因子变化，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。拟议的研究受到了吲唑-Cl强大的档案和令人鼓舞的初步结果的启发，这些结果证明了其在慢性MS小鼠模型中的治疗效果。具体而言，观察到内源性髓鞘再生的刺激和改善的轴突功能和神经学结果，并且似乎由增加的常驻OPC存活和分化介导。静止OPCs存在于MS病变中，并且不能被主要是免疫调节的当前MS药物有效激活。我们的目标是使用吲唑-Cl靶向内源性OPC，从而开发MS治疗，通过间歇性短期给药方案减缓疾病进展。

项目成果

Nudging oligodendrocyte intrinsic signaling to remyelinate and repair: Estrogen receptor ligand effects.

• DOI: 10.1016/j.jsbmb.2016.01.006
• 发表时间: 2016-06
• 期刊: The Journal of steroid biochemistry and molecular biology
• 作者: Khalaj AJ;Hasselmann J;Augello C;Moore S;Tiwari-Woodruff SK
• 通讯作者: Tiwari-Woodruff SK

Consistent induction of chronic experimental autoimmune encephalomyelitis in C57BL/6 mice for the longitudinal study of pathology and repair.

• DOI: 10.1016/j.jneumeth.2017.04.003
• 发表时间: 2017-06-01
• 期刊: Journal of neuroscience methods
• 影响因子: 3
• 作者: Hasselmann JPC;Karim H;Khalaj AJ;Ghosh S;Tiwari-Woodruff SK
• 通讯作者: Tiwari-Woodruff SK

Astrocyte Glutamate Uptake and Water Homeostasis Are Dysregulated in the Hippocampus of Multiple Sclerosis Patients With Seizures.

• DOI: 10.1177/1759091420979604
• 发表时间: 2020-01
• 期刊: ASN neuro
• 影响因子: 4.7
• 作者: Lapato AS;Thompson SM;Parra K;Tiwari-Woodruff SK
• 通讯作者: Tiwari-Woodruff SK

Chronic demyelination-induced seizures.

• DOI: 10.1016/j.neuroscience.2017.01.035
• 发表时间: 2017-03-27
• 期刊: Neuroscience
• 影响因子: 3.3
• 作者: Lapato AS;Szu JI;Hasselmann JPC;Khalaj AJ;Binder DK;Tiwari-Woodruff SK
• 通讯作者: Tiwari-Woodruff SK

Increase in chemokine CXCL1 by ERβ ligand treatment is a key mediator in promoting axon myelination.

• DOI: 10.1073/pnas.1721732115
• 发表时间: 2018-06-12
• 期刊: Proceedings of the National Academy of Sciences of the United States of America
• 影响因子: 11.1
• 作者: Karim H;Kim SH;Lapato AS;Yasui N;Katzenellenbogen JA;Tiwari-Woodruff SK
• 通讯作者: Tiwari-Woodruff SK