Role of Nitirc Oxide in Experimental Myasthenia Gravis

一氧化氮在实验性重症肌无力中的作用

基本信息

批准号：
7012263
负责人：
KEITH A KROLICK
金额：
$ 23.7万
依托单位：
UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
依托单位国家：
美国
项目类别：
财政年份：
2003
资助国家：
美国
起止时间：
2003-02-01 至 2009-01-31
项目状态：
已结题

项目摘要

DESCRIPTION (provided by applicant): Experimental Autoimmune Myasthenia Gravis (EAMG) is a neuromuscular disease that can be induced in rodents such as rats and mice by immunization with purified acetylcholine receptor (AChR). Neuromuscular dysfunction is associated with the production of autoantibodies directed at the AChR on the post-synaptic muscle membrane. The resulting abnormal function of the AChR leads to inefficient contractile function, muscle weakness and rapid fatigue characteristic of human MG. it is clear from both human and animal studies that antibody with reactivity against the AChR, although the most prominent disease determining factor, is not the only disease-determining factor. In addition, cytokines associated with the balance of TH1 vs TH2 activities may play an important role in the severity of disease symptoms in EAMG. In light of pilot studies presented below, it is likely that nitric oxide (NO), a potent immunomodulator capable of both beneficial and deleterious effects, may be a muscle-derived factor that could influence disease severity and progression. Therefore, it is the primary goal of this project to evaluate the potential of muscle-derived NO to influence disease progression in the rat model of EAMG. The general strategy to be used in this investigation is to seek links between iNOS/NO production and EAMG by monitoring skeletal muscle following in vivo exposures to immune mediators of EAMG (i.e., antibodies reactive with the acetylcholine receptor (AChR) and particular subsets of cytokine-producing cells). The Specific Aims of this project are as follows: Specific Aim 1. Evaluate INOS/NO-inducing activity associated with individual clonotypic ACHR-reactive antibody species of Lewis and WF rats. Specific Aim 2. Evaluate the ability of ACHR-reactive T cells to influence the expression of INOS/NO by rat skeletal muscle. Specific Aim 3. Determine influences of NO production on immune activities associated with EAMG. Specific Aim 4. Determine influences of NO production on the disease-susceptibility of the AChR-immune Lewis rat and the disease-resistance of the AChR-immune Wistar Furth rat.

描述（由申请人提供）：实验性自身免疫性肌无力重症（EAMG）是一种神经肌肉疾病，可以用纯化的乙酰胆碱受体（ACHR）免疫在啮齿动物（例如大鼠和小鼠）中诱导，可以诱导啮齿动物。神经肌肉功能障碍与针对后突触后肌肉膜上ACHR的自身抗体的产生有关。 ACHR产生的异常功能导致人Mg的收缩功能，肌肉无力和快速疲劳特征。从人类和动物研究中可以明显看出，对ACHR的反应性具有反应性，尽管最突出的疾病决定因素，但并不是唯一的疾病性因素。此外，与TH1与Th2活性平衡相关的细胞因子可能在EAMG中疾病症状的严重程度中起重要作用。鉴于下面介绍的试验研究，一氧化氮（NO）可能是一种具有有益和有害作用的有效免疫调节剂，可能是肌肉衍生的因素，可能会影响疾病的严重程度和进展。因此，该项目的主要目标是评估肌肉衍生的NO的潜力以影响EAMG大鼠模型中的疾病进展。在本研究中要使用的一般策略是通过监测EAMG免疫介质的体内暴露后（即，乙酰胆碱受体（ACHR）和细胞因子产生细胞的特定亚群反应抗体），通过监测骨骼肌和EAMG之间的联系。该项目的具体目的如下：特定目的1。评估与刘易斯和WF大鼠的clonotypic ACHR反应性抗体物种相关的INOS/NO诱导活性。具体目标2。评估ACHR反应性T细胞影响iNOS/NO的表达能力。具体目的3。确定无生产对与EAMG相关的免疫活性的影响。具体目的4。确定无生产对ACHR免疫刘易斯大鼠疾病敏感性的影响以及Achr-rmmune wistar furth大鼠的疾病抗性。