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致残的炎症性脱髓鞘疾病，影响着约35万美国人和全球超过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。目前，我们对多发性硬化症的影响因素的大部分知识都是基于实验性自身免疫性脑脊髓炎（EAE），一种多发性硬化症的动物模型。关于多发性硬化症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。近年来，我们对神经胶质成熟因子（glia maturity factor， GMF）的研究表明，GMF具有重要的免疫调节功能。最近，我们已经在小胶质细胞中建立了gmf依赖性炎症细胞因子/趋化因子的产生以及随后对少突胶质细胞（髓磷脂产生细胞）和神经元的破坏。基于GMF激活小胶质细胞和诱导几种已建立的促炎介质的能力，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，表明在主动转移模型和适应性转移模型中，缺乏内源性GMF可延迟EAE的发作并显著降低EAE的严重程度。我们的研究结果首次为靶向GMF治疗性干预多发性硬化提供了新的理论依据。本提案的目的是研究GMF对EAE的抑制作用，并阐明GMF作为治疗性干预多发性硬化的候选药物。本提案将探索一种有效抑制GMF在EAE中的功能的新治疗方法。基于我们最近在体外抑制GMF表达的成功，我们将在EAE小鼠中使用RNA干扰（RNAi）来抑制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，有效抑制转基因基因的功能将被证明是一种有效的策略，可以减缓甚至逆转EAE的致病过程。我们将追求两个具体目标。在Aim 1A中，我们将研究RNAi抑制EAE小鼠GMF表达的能力，并确定RNAi是否可以预防EAE。在Aim 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Aim 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：MS是一种致残的慢性炎症性脱髓鞘疾病，缺乏有效的治疗方法，这表明治疗这种毁灭性疾病的能力存在重大差距。本提案的目的是阐明GMF，一种公认的促炎介质，作为MS/EAE治疗干预的新候选物。这些研究可能为开发一种新的MS无毒治疗方法提供科学依据。

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.