DYSREGULATED 2-5A SYNTHETASE/RNASE L/PKR PATHWAYS IN CFS

描述（改编自研究者摘要）：研究 研究人员的实验室已经集中在两个dsRNA依赖性IFN- 可诱导的2 '5'寡A合成酶/RNA酶L和PKR途径。 他们有 报道了一种统计学上显著的失调，其中2 '5'A 合成酶以其活化形式存在，2 '5'A水平升高， RNase L上调，PKR表达下调。 最近的数据表明，外周血的其他独特差异 与正常人相比，CFS个体的单核细胞（PBMC） 对照 具体地，CFS PBMC中的这些发现是：1）36 kDa的 2 '5'被RNase L多克隆抗体识别的结合蛋白 抗体; 2）细胞肌动蛋白表达减少90%和3） 总蛋白质谱的显著变化。 这些数据将 研究人员在一个独特的位置，探索2 '5'A合成酶/核糖核酸酶 CFS中的L和PKR系统。 这项拟议中的研究将检查2 '5'A 合成酶和PKR途径在体外模型和来自队列的PBMC中的表达 CFS患者和两个对照人群，与 临床病理学 工作假设是， CFS的特征性体征和症状与 2 '5'A合成酶/RNase L和PKR途径的失调。 的 项目将解决：1）表达和活动的四个 2 '5'A合成酶的亚型; 2）2 '5'A合成酶的激活剂; 3） 细胞内浓度，寡聚体分布和稳定性 2 '5'A; 4）新发现的 36 kDa 2 '5'一种与RNase L免疫反应的结合蛋白 抗体; 5）用于抑制抗体的合成和天然途径。 CFS中上调的RNase L; 6） 上调RNase L活性和7）潜在的机制， PKR表达降低。 应用中的研究包括 建议有助于开发潜在的合理治疗方法 对于CFS。

DESCRIPTION (Adapted from investigator's abstract): Research in the investigator's laboratory has focused on the two dsRNA-dependent IFN- inducible 2'5'oligoA synthetase/RNase L and PKR pathways. They have reported a statistically significant dysregulation in which the 2'5'A synthetase is present in its activated form, 2'5'A levels are elevated, RNase L is upregulated and the expression of PKR is downregulated. Recent data suggest additional differences unique to peripheral blood mononuclear cells (PBMC) from individuals with CFS compared to normal controls. Specifically, these findings in CFS PBMC are: 1) a 36kDa 2'5'A binding protein which is recognized by an RNase L polyclonal antibody; 2) a 90% decrease in cellular actin expression and 3) a pronounced change in total protein profiles. These data place the investigator in a unique position to explore the 2'5'A synthetase/RNase L and PKR systems in CFS. The proposed research will examine the 2'5'A synthetase and PKR pathways in an in vitro model and PBMC from a cohort of CFS patients and two control populations, in association with clinical symptomatology. The working hypothesis is that the characteristic signs and symptoms of CFS are associated with the dysregulation of the 2'5'A synthetase/RNase L and PKR pathways. The project will address: 1) the expression and activities of the four isoforms of 2'5'A synthetase; 2) the activators of 2'5'A synthetase; 3) the intracellular concentration, oligomer distribution and stability of 2'5'A; 4) the identification and characterization of the newly-discovered 36 kDa 2'5'A binding protein that is immunoreactive with RNase L antibody; 5) synthetic and natural routes for the inhibition of the upregulated RNase L in CFS; 6) the ultimate implications of the upregulated RNase L activity and 7) potential mechanisms for the decreased expression of PKR. The studies in the application are suggested to contribute to development of potential rational therapies for CFS.