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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）患者的重要临床未满足需求