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GMF in CNS inflammation

GMF 在中枢神经系统炎症中的作用

基本信息

批准号：
8197792
负责人：
ASGAR ZAHEER
金额：
$ 32.16万
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
起止时间：
2004-07-01 至 2013-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8197792
关键词：
Adoptive Transfer Affect American Animal Model Antibodies Astrocytes Atrophic Autoimmune Process Axon Brain C57BL/6 Mouse Cells Chronic Chronic Phase Clinical Clinical Trials Culture Media Data Demyelinating Diseases Demyelinations Development Disease Experimental Autoimmune Encephalomyelitis Free Radicals Functional disorder Glia Maturation Factor Goals Grant Granulocyte-Macrophage Colony-Stimulating Factor Immune In Vitro Incidence Individual Inflammation Inflammation Mediators Inflammatory Knowledge Laboratories Lead MAP Kinase Gene MAPK14 gene Mediating Mediator of activation protein Microglia Modeling Molecular Profiling Multiple Sclerosis Mus Myelin Myelin Sheath NF-kappa B NFKB Signaling Pathway Neurons Nitrogen Oligodendroglia One-Step dentin bonding system Oxygen Paralysed Pathogenesis Pathway interactions Patients Peptides Phase Preventive Intervention Process Production Progressive Disease Proteins RNA Interference Relapse Research SJL/J Mouse Severities Signal Transduction Small Interfering RNA Spinal Cord Spleen Stress T-Lymphocyte Testing Therapeutic Therapeutic Intervention Time Tissues Toxic effect abstracting base beneficiary brain cell central nervous system demyelinating disorder chemokine cytokine effective therapy illness length macrophage mitogen-activated protein kinase p38 novel novel therapeutic intervention oligodendrocyte-myelin glycoprotein prevent response small hairpin RNA success theories vector

项目摘要

Abstract Multiple sclerosis (MS) is a disabling inflammatory demyelinating disease of the central nervous system that affects an estimated 350,000 Americans and over a million individuals worldwide. Since the pathogenesis of MS is not clear, no definitive treatment is as of yet available. Much of our current knowledge about contributing factors of MS is based on experimental autoimmune encephalomyelitis (EAE), an animal model of MS. Several theories for the pathogenesis of MS exist and implicate infiltrating T cells, pro-inflammatory cytokines, chemokines, activated microglia and astrocytes. Our research efforts in recent years on glia maturation factor (GMF), a protein isolated, sequenced and cloned in our laboratory, have demonstrated a major immunomodulatory function of GMF. Recently, we have established the GMF-dependent production of inflammatory cytokines/chemokines in microglia and the subsequent destruction of oligodendroglia (myelin producing cells) and neurons. Based on GMF's ability to activate microglia and induce several well- established pro-inflammatory mediators, we hypothesize that GMF is involved in the pathogenesis of MS/EAE. We have also provided strong experimental evidence using GMF-deficient mice, that an absence of endogenous GMF delays the onset and drastically reduces the severity of EAE, in both active and adaptive transfer models. Our results provided for the first time a novel rational for targeting GMF for therapeutic intervention in MS. The objective of this proposal is to study the effect of GMF inhibition in EAE and to elucidate GMF as a candidate for therapeutic intervention in MS. This proposal will investigate a novel therapeutic approach to effectively suppress GMF-function in EAE. Building on our recent success in suppressing GMF expression in vitro, we will use RNA interference (RNAi) to suppress GMF expression and an anti-GMF antibody to neutralize endogenous GMF protein in EAE mice. Our hypothesis is that the effective suppression of GMF-function will prove to be an effective strategy to slow, and perhaps reverse pathogenic processes in EAE. We will pursue two Specific Aims. In Aim 1A, we will study the ability of RNAi to suppress GMF expression in EAE mice and determine whether RNAi can prevent EAE. In Aim 1B, we will test whether the delivery of a neutralizing anti-GMF antibody to EAE mice will prevent or reverse pathological hallmarks of EAE. In Aim 2, we will compare these two GMF-suppression strategies in the context of CNS inflammation.

摘要