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.

抽象的多发性硬化症（MS）是一种致命的中枢神经系统炎症性脱髓鞘疾病这影响了估计有35万美国人和全球超过一百万个人。由于发病机理 MS尚不清楚，尚无确切的治疗方法。我们目前关于 MS的促成因素基于实验自身免疫性脑脊髓炎（EAE），这是一种动物模型多发性硬化症。 MS发病机理的几种理论存在并暗示浸润的T细胞，促炎细胞因子，趋化因子，活化的小胶质细胞和星形胶质细胞。近年来我们关于神经胶质的研究工作成熟因子（GMF）是一种分离，测序和克隆在我们实验室中的蛋白 GMF的主要免疫调节功能。最近，我们建立了依赖GMF的生产小胶质细胞中的炎性细胞因子/趋化因子和随后的寡胶质细胞破坏（髓磷脂产生细胞）和神经元。基于GMF激活小胶质细胞并诱导几种良好的能力既定的促炎性介体，我们假设GMF参与了MS/EAE的发病机理。我们还使用GMF缺陷小鼠提供了有力的实验证据，没有内源性GMF在主动和适应性的转移模型。我们的结果首次提供了针对GMF治疗的新颖理性干预MS。该提案的目的是研究GMF抑制在EAE和阐明GMF作为MS治疗干预的候选者。该提议将调查一部小说有效抑制EAE中GMF功能的治疗方法。基于我们最近的成功在体外抑制GMF表达，我们将使用RNA干扰（RNAI）抑制GMF表达和一种抗GMF抗体，可中和EAE小鼠内源性GMF蛋白。我们的假设是有效抑制GMF功能将被证明是慢速且可能反向致病性的有效策略 EAE的过程。我们将追求两个具体的目标。在AIM 1A中，我们将研究RNAi抑制的能力 EAE小鼠中的GMF表达并确定RNAi是否可以预防EAE。在AIM 1B中，我们将测试是否对EAE小鼠的中和抗GMF抗体的递送将预防或逆转病理标志伊。在AIM 2中，我们将在中枢神经系统发炎的背景下比较这两种GMF抑制策略。