GMF in CNS inflammation

描述（由申请人提供）：多发性硬化症（MS）是一种中枢神经系统的致残性炎性脱髓鞘疾病，估计影响35万美国人和全球超过一百万人。由于MS的发病机制尚不清楚，目前尚无明确的治疗方法。我们目前的知识MS的贡献因素是基于实验性自身免疫性脑脊髓炎（EAE），MS的动物模型。MS的发病机制存在几种理论，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。胶质成熟因子（GMF）是本实验室分离、测序和克隆的一种蛋白质，近年来的研究表明GMF具有重要的免疫调节功能。最近，我们已经建立了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的少突胶质细胞（髓鞘产生细胞）和神经元的破坏。基于GMF激活小胶质细胞和诱导几种公认的促炎介质的能力，我们假设GMF参与MS/EAE的发病机制。我们还提供了强有力的实验证据，使用转基因食品缺陷小鼠，缺乏内源性转基因食品延迟发病，并大大降低EAE的严重程度，在主动和适应性转移模型。我们的研究结果首次提供了一种新的合理的靶向转基因食品的治疗干预MS。本建议的目的是研究EAE中的转基因食品抑制的效果，并阐明转基因食品作为一个候选人的治疗干预MS。本建议将探讨一种新的治疗方法，有效地抑制转基因食品的功能在EAE。基于我们最近在体外抑制GMF表达方面的成功，我们将使用RNA干扰（RNAi）来抑制GMF表达，并使用抗GMF抗体来中和EAE小鼠中的内源性GMF蛋白。我们的假设是，GMF功能的有效抑制将被证明是一种有效的策略，以减缓，甚至逆转EAE的致病过程。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小鼠递送中和抗转基因抗体是否会预防或逆转EAE的病理学特征。在目标2中，我们将在CNS炎症的背景下比较这两种GMF抑制策略。公共卫生相关性：MS是一种致残性慢性炎性脱髓鞘疾病，缺乏有效的治疗方法，这代表了治疗这种毁灭性疾病的能力存在重大差距。该建议的目的是阐明GMF，一种成熟的促炎介质，作为MS/EAE治疗干预的新候选物。这些研究可能为开发MS的新型无毒治疗提供科学依据。

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.