New Strategies to Decipher the Pathophysiology of Chronic Fatigue Syndrome

描述（由申请人提供）：慢性疲劳综合征（CFS）是一种复杂的疾病，估计在西方世界影响0.5%-2%的人口。其发病机制被认为涉及遗传和环境（包括病毒）成分，如其他慢性炎症性疾病，如多发性硬化症、类风湿性关节炎和动脉粥样硬化。与这种慢性炎症背景相一致，已知CFS患者寿命缩短，并且有发生淋巴瘤的风险。我们推测，在易感宿主遗传背景下，多种病毒的活动性和复发性感染引起的慢性炎症刺激导致了以CFS为特征的发病机制。本研究项目的总体目标是确定欧洲和美国CFS患者队列中与不同疾病表型相关的病毒和宿主参数，包括美国队列中一个亚组中套细胞淋巴瘤（MCL）的发展。在目的1中，我们将识别和确认欧洲和美国CFS患者队列中的新型病毒感染。1.1)我们将使用两种互补的方法来检测新型病毒mRNA：大规模平行特征测序（MPSS）和定制DNA微阵列。1.2)采用定量聚合酶链反应Q-PCR确认病毒基因表达。1.3)将开发永生化细胞系来分离病毒并阐明病毒与宿主细胞基因表达之间的联系。在目标2中，我们将阐明易感性的遗传因素和宿主防御系统的失调。具体而言，我们将确定：2.1)先前确认在CFS中差异表达的88个人类基因的PBMC基因表达2.2)在Luminex平台上使用多重悬浮抗体阵列的血清趋化因子和细胞因子谱2.3)HLA、KIR基因型和全基因组SNP谱2.4)I型干扰素信号通路的缺陷。在每个子目标中，将使用在多个时间点从个体患者和我们独特且广泛的样本库中提取的血清和PBMC样本，将两个队列与正常和疾病对照进行比较。该研究将为CFS患者不同亚群的治疗和诊断策略的发展提供必要的信息，并可能确定新的病毒关联、遗传特征和生物标志物，从而可以预测MCL的发展，从而使预防性治疗成为可能。公共卫生相关性：拟议的研究将为慢性疲劳综合征的发病机制提供重要的见解，因此可以开发准确的测试和特定的治疗方法，以治愈疾病和预防危及生命的并发症。

DESCRIPTION (provided by applicant): Chronic Fatigue Syndrome (CFS) is a complex disease estimated to affect between 0.5%-2% of the population in the Western world. Its pathogenesis is thought to involve both inherited and environmental (including viral) components, as with other chronic inflammatory diseases such as, multiple sclerosis, rheumatoid arthritis, and atherosclerosis. Consistent with this chronic inflammatory context, CFS patients are known to have a shortened life-span and are at risk for developing lymphoma. We hypothesize that chronic inflammatory stimulation from active and recurrent infections of multiple viruses on a susceptible host genetic background leads to the pathogenesis characterized by CFS. The overall goal of this research project is to define these viral and host parameters in European and American cohorts of CFS patients that correlate with distinct disease phenotypes, including the development of mantle cell lymphoma (MCL) in a subgroup of the American cohort. In Aim 1) we will identify and confirm novel viral infections in European and American CFS patient cohorts. 1.1) we will use two complementary methods for detection of novel virus mRNA: massive parallel signature sequencing (MPSS) and a custom DNA microarray. 1.2) Quantitative polymerase chain reaction Q-PCR will be used for confirmation of virus gene expression. 1.3) immortalized cell lines will be developed to isolate virus and elucidate links between virus and host cell gene expression. In Aim 2), we will elucidate genetic factors of susceptibility and the dysregulation of the host defense system. Specifically, we will determine: 2.1) PBMC gene expression of 88 human genes previously confirmed as being differentially expressed in CFS 2.2) serum chemokine and cytokine profiles using multiplex suspension antibody arrays on a Luminex platform 2.3) HLA, KIR genotypes and whole genome SNP profiles 2.4) Defects in the type I Interferon signaling pathway. In each subaim both cohorts will be compared to normal and disease controls using specimens of serum and PBMC taken at multiple time-points from individual patients and taken from our unique and extensive sample repository. This study will provide information necessary for development of treatment and diagnostic strategies for distinct subgroups of CFS patients, and may identify novel virus associations, genetic signatures and biomarkers, which can predict the development of MCL, thus enabling use of preventive therapeutics. PUBLIC HEALTH RELEVANCE: The proposed research will provide significant insight into the disease mechanisms of Chronic Fatigue Syndrome so accurate testing and specific treatments can be developed with a goal of curing the disease and preventing life-threatening complications.