Defining mechanisms of disease and repair in a viral model of multiple sclerosis

定义多发性硬化症病毒模型中的疾病和修复机制

基本信息

批准号：
10640816
负责人：
Thomas E Lane
金额：
$ 87.41万
依托单位：
UNIVERSITY OF CALIFORNIA-IRVINE
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-05-01 至 2029-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10640816
关键词：
Ablation Animal Model Area Axon C57BL/6 Mouse CRISPR/Cas technology Cell Communication Cell Culture Techniques Cell Maturation Cells Clinical Demyelinating Diseases Demyelinations Disease Disease Progression Engraftment Event Generations Genes Goals Human Immune Infection Laboratories MHV-JHM Mediating Methods Microglia Modeling Molecular Motor Multiple Sclerosis Murine hepatitis virus Mus Nuclear RNA Oligodendroglia Operative Surgical Procedures Pathogenesis Patients Predisposition Procedures Research Research Proposals Severities Signal Pathway Signal Transduction Therapeutic Intervention Untranslated RNA Viral Visualization associated symptom axon injury chemokine genetic approach immune cell infiltrate improved insight multiple sclerosis patient nerve stem cell neuroinflammation new therapeutic target oligodendrocyte progenitor pre-clinical remyelination repaired transcriptome sequencing two photon microscopy virus-induced demyelination

项目摘要

Abstract: An important unmet clinical need for patients with the demyelinating disease multiple sclerosis (MS) is an effective method for promoting remyelination that can ameliorate clinical symptoms associated with demyelination and restore motor function while limiting immune cell infiltration into the CNS. The long-term objectives of this research proposal are to i) define how chemokine signaling controls neuroinflammation and disease progression, ii) assess the effects of chemokine signaling in regulating oligodendrocyte progenitor cell (OPC) maturation and remyelination, iii) further characterize how engrafted human and mouse neural progenitor cells enhance axonal integrity, promote remyelination and influence neuroinflammation/demyelination, iv) define mechanisms by which microglia restrict the severity of demyelination and influence remyelination. To accomplish these goals, we will use a well-accepted pre-clinical animal models of MS. For over 20 years, my laboratory has used intracranial infection of susceptible C57BL/6 mice with the neuroadapted JHM strain of mouse hepatitis virus (JHMV) as a model of viral-induced demyelination to study molecular and cellular events controlling neurioinflammation, demyelination, and remyelination. Proposed experimental procedures that will aid in accomplishing our research goals will include genetic approaches through generation of mice in which targeted genes are either selectively induced/ablated to assess effect on disease progression and repair, CRISPR technology to ablate specific target genes in NPC cultures, single cell and nuclear RNA sequencing on immune cells and resident CNS cells and use of 2-photon (2P) microscopy to visualize axonal damage/repair and remyelination. Collectively, we believe our experimental goals outlined in this proposal will provide new insight into the pathogenesis of MS as well as identify new targets for therapeutic intervention to impede disease progression and promote remyelination.

摘要：脱髓鞘疾病多发性硬化症（MS）患者的一个重要的未满足的临床需求是促进髓鞘再生的有效方法，可以改善与髓鞘再生相关的临床症状脱髓鞘并恢复运动功能，同时限制免疫细胞浸润到中枢神经系统。长期来看本研究计划的目标是 i) 定义趋化因子信号如何控制神经炎症和疾病进展，ii) 评估趋化因子信号传导在调节少突胶质细胞祖细胞中的作用 (OPC) 成熟和髓鞘再生，iii) 进一步表征人类和小鼠神经移植的方式祖细胞增强轴突完整性，促进髓鞘再生并影响神经炎症/脱髓鞘，iv) 定义了小胶质细胞限制神经炎症/脱髓鞘严重程度的机制脱髓鞘并影响髓鞘再生。为了实现这些目标，我们将使用广为接受的临床前 MS的动物模型。 20多年来，我的实验室一直使用易感C57BL/6的颅内感染小鼠肝炎病毒 (JHMV) 神经适应性 JHM 株作为病毒诱导的模型脱髓鞘研究控制神经炎症、脱髓鞘和神经炎症的分子和细胞事件髓鞘再生。有助于实现我们研究目标的拟议实验程序将包括通过产生小鼠的遗传方法，其中目标基因被选择性诱导/消除为了评估对疾病进展和修复的影响，CRISPR技术消除鼻咽癌中的特定靶基因对免疫细胞和常驻中枢神经系统细胞进行培养、单细胞和核 RNA 测序以及 2 光子的使用 (2P) 显微镜观察轴突损伤/修复和髓鞘再生。总的来说，我们相信我们的该提案中概述的实验目标将为 MS 的发病机制以及确定治疗干预的新目标，以阻止疾病进展并促进髓鞘再生。