中枢神经系统炎症中的神经胶质成熟因子-猫眼课题宝

中枢神经系统炎症中的神经胶质成熟因子

批准号：

7238669

负责人：

ASGAR ZAHEER

金额：

$32.34万

依托单位：

UNIVERSITY OF IOWA

依托单位国家：

美国

项目类别：

财政年份：

2004

资助国家：

美国

项目状态：

已结题

起止时间：

2004-07-01 至 2009-01-14

来源：

https://reporter.nih.gov/project-details/7238669

关键词：

Address Adoptive Transfer Affect Age Alzheimer&apos s Disease American Animal Model Animals Antibodies Antigen-Presenting Cells Antigens Astrocytes Atrophic Autoimmune Process Axon Binding Biological Assay Blinded Brain CCL2 gene CD4 Positive T Lymphocytes CXCL10 gene Cell Separation Cells Centrifugation Chromosomes, Human, Pair 14 Chronic Chronic Phase Clinical Condition Conditioned Culture Media Control Animal Control Groups Core Facility DNA Microarray Chip DNA Microarray format Data Degenerative Disorder Demyelinations Development Disease Dominant-Negative Mutation EMSA Embryo Encephalomyelitis Equipment Experimental Autoimmune Encephalomyelitis Experimental Designs Female Figs - dietary Flow Cytometry Free Radicals Functional disorder Gene Expression Genes Genotype Glia Maturation Factor Glial Fibrillary Acidic Protein Goals Histologic Histology Histopathology Human Immune Immune response Immunization Immunoprecipitation Immunosuppressive Agents In Vitro Incidence Individual Infiltration Inflammation Inflammatory Interleukin-1 beta Interleukin-12 Investigation Iowa Knock-out Knockout Mice Knowledge Laboratories Laboratory Animals Letters Limb structure Lymphocyte MAP Kinase Gene MAPK14 gene Macrophage Inflammatory Protein-1 Major Histocompatibility Complex Measures Mediating Mediator of activation protein Methodology Methods Microarray Analysis Microglia Microscopy Modeling Molecular Molecular Profiling Mononuclear Morbidity - disease rate Multiple Sclerosis Mus Myelin Myelin Sheath NF-kappa B Neuraxis Neuroglia Neurologic Neurons Newborn Infant Nitrogen Numbers Oligodendroglia Oligonucleotides Outcome Oxygen Paralysed Parkinson Disease Pathogenesis Pathologic Pathway interactions Patients Percoll Peripheral Pertussis Toxin Phase Phosphotransferases Platelet Factor 4 Play Prevention Principal Investigator Procedures Process Production Protein Overexpression Proteins Purpose Recovery Relapse Reporting Research Research Personnel Role Sampling Schwann Cells Score Severities Severity of illness Signal Transduction Sorting - Cell Movement Specificity Spinal Cord Staging Standards of Weights and Measures Stress Study Section Suggestion Surveys T-Lymphocyte TNF gene Techniques Testing Therapeutic Intervention Time Time Study Tissues Toxic effect Transgenes Transgenic Mice Trauma Universities Week Wild Type Mouse Woman base behavior test beneficiary brain cell central nervous system demyelinating disorder chemokine cytokine day design disability experience functional restoration genome sequencing granulocyte human MAPK14 protein interleukin-12 subunit p40 interleukin-23 macrophage male mitogen-activated protein kinase p38 mortality mutant neutralizing antibody promoter reconstitution research facility research study response theories tool upstream kinase young adult

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DESCRIPTION (provided by applicant): Elucidation of the molecular mechanisms that regulate inflammation in the central nervous system (CNS) is critical to our understanding of a broad spectrum of diseases, including multiple sclerosis, Alzheimer's, and Parkinson's. These diseases are responsible for significant morbidity and mortality, and new prevention and treatment approaches are urgently needed. This proposal builds on our recent finding that glia maturation factor (GMF), a highly conserved protein unique to the brain, serves as an important immune modulator by promoting the production and secretion of pro-inflammatory cytokines leading to the activation of microglia, the antigen presenting cells in the brain. The Human Genome Sequence Consortium has identified the gene of GMF in chromosome 14. In this proposal, we will study experimental autoimmune encephalomyelitis (EAE), the standard animal model for multiple sclerosis, with the hypothesis that GMF contributes to the pathogenesis of EAE. This research will include investigations on the already available GMF knockout mice, wild type mice, and GMF transgenic mice (in the final stages of development) in which GMF transgene will be reintroduced in GMF knockout mice under the influence of astrocyte-specific GFAP promoter. This will provide, for the first time, a unique opportunity to study the pathogenesis of EAE in the contrasting settings of no GMF, normal amount of GMF, and high expression of GMF. AIM I: To study the effects of GMF on the two major signal transduction cascades involved in CNS inflammation and immune processes, namely, the p38 MAP kinase and JAK/STAT pathways. We will utilize cultured brain cells, astrocytes, microglia and oligodendroglia, derived from GMF knockout versus wild type mice. AIM II: To study the role of GMF in the pathophysiology of EAE and to establish that the absence of GMF mitigates the severity of the disease. (A) GMF knockout and wild type mice will be challenged with the proper antigen to induce EAE. The development and the histopathology of the brain and spinal cord at various stages of the disease will be compared. (B) To evaluate the expression profiles of cytokines and the free radical generating mediators during the progression of EAE in the brain, spinal cord and in isolated mononuclear cells. Knowledge obtained from this study can also be applied to degenerative diseases of the brain where microglial activation plays an important role, such as Alzheimer's and Parkinson's.

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