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Mechanisms by which effector T cells modulate endogenous remyelination

效应T细胞调节内源性髓鞘再生的机制

基本信息

批准号：
10526405
负责人：
PETER A CALABRESI
金额：
$ 49.88万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2000
资助国家：
美国
起止时间：
2000-07-01 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10526405
关键词：
Adaptive Immune System Address Adopted Adoptive Transfer Affect Agonist Antigen Presentation Antigens Area Astrocytes Autopsy Axon Brain CD4 Positive T Lymphocytes CD8-Positive T-Lymphocytes CD8B1 gene Cell Count Cell Differentiation process Cell Survival Cell physiology Cell secretion Cells Cellular biology Central Nervous System Cephalic Chronic Clinic Cross Presentation Cues Cuprizone Cytokine Signaling Demyelinations Development Disease Drug Targeting Experimental Autoimmune Encephalomyelitis Failure Funding Genetic Genetic Transcription Globulins Grant Immune Immunotherapy In Vitro Inflammation Inflammatory Interferon Type II Kinetics Knowledge Laboratories Lentivirus Lymphocyte Lymphocyte Activation Lymphoid MHC Class I Genes Maps Mediating Meningeal Microglia Modeling Molecular Multiple Sclerosis Mus Myelin NF-kappa B NFKB Signaling Pathway Neuroglia Neurologic Neurons Non-Insulin-Dependent Diabetes Mellitus Nuclear Hormone Receptors Oligodendroglia Paper Pathogenicity Pathology Pathway interactions Peripheral Pharmaceutical Preparations Phenotype Process Property Receptor Signaling Refractory Regulatory Pathway Relapsing-Remitting Multiple Sclerosis Reporter Research Role Signal Pathway Signal Transduction Signaling Molecule Site System T cell infiltration T-Cell Activation T-Lymphocyte T-Lymphocyte Subsets Therapeutic Therapeutic Intervention Thinking Thinness Trauma brain tissue cell motility chemokine cytotoxic cytotoxic CD8 T cells cytotoxicity disability effector T cell exenatide immune function in vivo inflammatory milieu intravital microscopy lymphocyte trafficking neuroprotection neurotoxic new therapeutic target novel novel therapeutic intervention oligodendrocyte precursor pharmacologic precursor cell remyelination repaired response single-cell RNA sequencing success targeted treatment therapy development tissue injury trafficking two-photon young adult

项目摘要

Project Summary: The project addresses an important problem - multiple sclerosis (MS), which is the most common cause of neurological disability in young adults after trauma. While the approval of numerous immunotherapies has had an impact on reducing inflammatory disease activity in relapsing remitting MS, there are no therapies to date that enhance repair of the myelin or markedly influence the progressive stage of the disease. Although non-inflammatory mechanisms may contribute to progressive MS, several recent papers highlight a critical role for ongoing inflammation within the brain at or next to sites of tissue injury. A direct pathogenic role for T cells in progressive MS has been suggested by the presence of lymphoid meningeal follicles, which are associated with cortical demyelination and thinning. A more detailed understanding of how immune cells inhibit remyelination is critical for developing therapies to enhance remyelination and halt progressive MS. Despite observational evidence that immune cells may suppress or promote remyelination, there is remarkably little known regarding the specific mechanisms by which these processes occur. This project addresses a barrier to progress in the field because our understanding of why remyelination fails in disease is presently limited because we have not elucidated the pathways involved in failed oligodendrocyte precursor cell (OPC) differentiation. We plan to pursue an exciting novel observation that not only do OPCs fail to differentiate into myelin producing cells, but in an inflammatory environment they adopt an immune phenotype (iOPCs) and can prime CD8 T cells, as well as become targets of the cytotoxic lymphocytes (CTL). This represents a paradigm shift in thinking about OPC biology and remyelination. We will characterize the profile, fate and function of iOPC. We seek to understand the mechanisms by which they activate CD8 T cells that in turn kill a subset of the iOPC as target cells. We will track iOPC using fate mapping strategies and two-photon intravital microscopy through cranial windows. We aim to develop drug therapies that target the NFkB signaling pathway involved in MHC expression using several novel therapeutic approaches including the type 2 diabetes mellitus drug exenatide and an agonist of the NLRX-1 signaling molecule that normally regulates NFkB expression.

项目总结: