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) 是一种致残性中枢神经系统炎症性脱髓鞘疾病据估计，这影响了 35 万美国人和全世界超过 100 万人。发病以来 MS 的发病机制尚不清楚，目前尚无明确的治疗方法。我们目前的大部分知识是关于 MS 的影响因素基于实验性自身免疫性脑脊髓炎 (EAE)，这是一种多发性硬化症。存在多种关于多发性硬化症发病机制的理论，并暗示浸润性 T 细胞、促炎细胞细胞因子、趋化因子、活化的小胶质细胞和星形胶质细胞。我们近年来在胶质细胞方面的研究工作成熟因子 (GMF) 是一种在我们实验室分离、测序和克隆的蛋白质，已证明 GMF的主要免疫调节功能。最近，我们建立了依赖转基因食品的生产小胶质细胞中的炎症细胞因子/趋化因子以及随后的少突胶质细胞（髓鞘质）的破坏产生细胞）和神经元。基于 GMF 激活小胶质细胞并诱导多种良好- 确定了促炎介质后，我们假设 GMF 参与了 MS/EAE 的发病机制。我们还通过使用 GMF 缺陷小鼠提供了强有力的实验证据，表明缺乏内源性 GMF 可以延迟 EAE 的发作并大大降低主动性和适应性 EAE 的严重程度转移模型。我们的结果首次为靶向 GMF 治疗提供了新的理论依据干预多发性硬化症。本提案的目的是研究 GMF 抑制对 EAE 的影响并阐明 GMF 作为 MS 治疗干预的候选者。该提案将调查一部小说有效抑制 EAE 中 GMF 功能的治疗方法。以我们最近的成功为基础体外抑制GMF表达，我们将使用RNA干扰（RNAi）来抑制GMF表达并一种抗 GMF 抗体，可中和 EAE 小鼠的内源性 GMF 蛋白。我们的假设是，有效抑制 GMF 功能将被证明是减缓甚至逆转致病性的有效策略 EAE 中的流程。我们将追求两个具体目标。在目标 1A 中，我们将研究 RNAi 抑制的能力 EAE小鼠中GMF的表达并确定RNAi是否可以预防EAE。在目标 1B 中，我们将测试是否向 EAE 小鼠递送中和性抗 GMF 抗体将预防或逆转 EAE 小鼠的病理特征 EAE。在目标 2 中，我们将在中枢神经系统炎症的背景下比较这两种 GMF 抑制策略。