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

描述(改编自调查人员摘要)： 研究人员的实验室专注于两种依赖dsRNA的干扰素- 可诱导的2‘5’寡核苷酸合成酶/核糖核酸酶L和PKR通路。他们有 报告了一种统计上显著的失调，其中2‘5’A 合成酶以激活形式存在，2‘5’A水平升高， 核糖核酸酶L表达上调，PKR表达下调。 最近的数据表明，外周血液存在其他独有的差异 CFS患者外周血单个核细胞(PBMC)与正常人的比较 控制。具体地说，在CFS PBMC中的这些发现是：1)36 kDa 核糖核酸酶L多克隆识别的2‘5’结合蛋白 抗体；2)细胞肌动蛋白表达减少90%；3)a 总蛋白质谱发生了显著变化。这些数据将 研究人员以独特的地位探索2‘5’A合成酶/核糖核酸酶 L与CFS中的PKR系统。拟议的研究将审查2‘5’A 体外模型中的合成酶和PKR通路以及队列中的PBMC CFS患者和两个对照人群之间的关系 临床症状学。工作假说是， 慢性疲劳综合征的特征症状和体征与 2‘5’A合成酶/核糖核酸酶L和PKR通路的失调这个 项目将涉及：1)四个方面的表达和活动 2)2‘5’A合成酶的激活物； 低聚物在细胞内的浓度、分布和稳定性 2‘5’A；4)新发现的 与核糖核酸酶L免疫反应的36 kDa 2‘5’结合蛋白 抗体；5)合成和天然途径抑制 上调了CFS中的核糖核酸酶L；6) 上调核糖核酸酶L活性和7)可能的机制 PKR表达降低。应用程序中的研究包括 建议为开发潜在的合理治疗方法做出贡献 用于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.