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：
7997168
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/7997168
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 Health 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 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

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: The lack of effective treatments for MS, a disabling chronic inflammatory demyelinating disease, represents a significant gap in the ability to treat this devastating disease. The aim of this proposal is to elucidate GMF, a well-established pro-inflammatory mediator, as a novel candidate for therapeutic intervention in MS/EAE. These studies may provide the scientific rationale for the development of a novel non-toxic therapy for MS.

描述（由申请人提供）：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，影响估计 350,000 名美国人和全世界超过 100 万人。由于多发性硬化症的发病机制尚不清楚，目前尚无明确的治疗方法。我们目前对多发性硬化症影响因素的大部分了解都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的动物模型。存在多种关于多发性硬化症发病机制的理论，这些理论涉及浸润性 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，我们对神经胶质成熟因子（GMF）（一种在我们实验室分离、测序和克隆的蛋白质）的研究工作证明了 GMF 的主要免疫调节功能。最近，我们已经确定小胶质细胞中炎症细胞因子/趋化因子的GMF依赖性产生以及随后对少突胶质细胞（产生髓磷脂的细胞）和神经元的破坏。基于 GMF 激活小胶质细胞并诱导几种成熟的促炎介质的能力，我们假设 GMF 参与 MS/EAE 的发病机制。我们还使用 GMF 缺陷小鼠提供了强有力的实验证据，表明在主动和适应性转移模型中，内源性 GMF 的缺乏会延迟 EAE 的发作并大大降低 EAE 的严重程度。我们的研究结果首次为针对多发性硬化症治疗干预的 GMF 提供了新的理论依据。该提案的目的是研究 GMF 抑制对 EAE 的影响，并阐明 GMF 作为 MS 治疗干预的候选药物。该提案将研究一种有效抑制 EAE 中 GMF 功能的新治疗方法。基于我们最近在体外抑制 GMF 表达方面取得的成功，我们将使用 RNA 干扰 (RNAi) 来抑制 EAE 小鼠中的 GMF 表达，并使用抗 GMF 抗体来中和内源性 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 EAE 致病过程的有效策略。我们将追求两个具体目标。在目标 1A 中，我们将研究 RNAi 抑制 EAE 小鼠中 GMF 表达的能力，并确定 RNAi 是否可以预防 EAE。在目标 1B 中，我们将测试向 EAE 小鼠递送中和性抗 GMF 抗体是否会预防或逆转 EAE 的病理特征。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。公共卫生相关性：多发性硬化症是一种致残性慢性炎症性脱髓鞘疾病，缺乏有效的治疗方法，表明治疗这种破坏性疾病的能力存在巨大差距。该提案的目的是阐明 GMF（一种成熟的促炎介质）作为 MS/EAE 治疗干预的新候选者。这些研究可能为开发多发性硬化症新型无毒疗法提供科学依据。