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

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：当前可用的免疫调节疗法建立后不会调节轴突变性的发病机理，并且仅部分有效地防止MS患者的永久残疾发作。鉴定刺激内源性髓鞘形成的药物并释放轴突变性，理论上会降低疾病进展的速度。我们先前已经表明，用雌激素受体处理脱髓鞘的小鼠模型（ER）ß配体；日二叶二硫二替二氮具有履行这一角色的潜力。因为DPN是一种普通的eRß配体，其特异性较低，因此较高特异性ERB，发现吲哚唑-CL是最好的Erß配体。目的是在多发性硬化症（MS）动物模型中实现体内原理证明，以确定候选idazole-Cl用于MS治疗的可行性。使用最佳剂量方案，预计吲唑-CL对刺激内源性少突胶质细胞（OL）祖细胞（OPC）生存和分化，轴突再髓和神经保护的直接影响。动作机制将通过第二信使信号传导和目标细胞类型进行研究。与翻译相关的成像将用于可视化效果N慢性MS小鼠模型。此外，将评估吲唑-CL诱导的血清细胞因子变化和生长因子的变化，以确认潜在的生物标志物和临床应用。最终，将进行支持临床前候选提名和档案完成的安全研究。拟议的研究的灵感来自Idazole-CL强大的档案和令人鼓舞的初步结果，证明了其在慢性MS小鼠模型中的治疗效率。具体而言，观察到内源性透明度和改善的轴突功能的刺激，并观察到神经系统结局，并且似乎是由OPC存活和分化增加的居民介导的。 MS病变中存在静止的OPC，并且不会在很大程度上被免疫调节的当前MS药物有效地激活。我们旨在使用吲唑-CL靶向内源性OPC，从而开发MS治疗，以间歇性，短期给药方案减慢疾病进展。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

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
影响因子：
0
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