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：
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
项目类别：
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

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

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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)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）：当前可用的免疫调节疗法一旦建立后，就不会调节轴突变性的发病机理，并且仅在防止MS患者的永久性残疾发作方面有效地有效。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（ER）B配体处理脱髓鞘模型。日二叶二硫二替二氮具有履行这一角色的潜力。因为DPN是一种较低特异性的通用ERB配体，我们筛选出更高的特异性ERB，发现吲唑-CL是最好的ERB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，并令人鼓舞的初步结果证明了其在慢性MS小鼠模型中的治疗功效。具体而言，观察到内源性再生和改善的轴突功能的刺激和改善的轴突功能，并通过增加的OPC存活和分化而介导。 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。