Long non-coding RNA signatures to classify multiple sclerosis

 描述(申请人提供)：多发性硬化症[MS]的诊断取决于临床症状和检查，并有适当的磁共振成像结果或其他实验室测试支持，如脑脊液中的寡克隆带和诱发电位测试。临床隔离综合征(CIS)是持续至少24小时的首发神经系统疾病 可能由局灶性炎症或脱髓鞘引起。美国每年大约有10,000-15,000例多发性硬化症的新诊断病例。每年经历CIS的人数大约是这个数字的2-3倍，这表明经历CIS的受试者远远多于发展为MS的受试者，确定患有CIS的受试者是否会发展为多发性硬化症的医疗成本是显着的。此外，多发性硬化症的误诊给我们的医疗系统带来了巨大的成本负担，因为这是一种频繁的事件，随着新旧疗法的成本不断上升，管理多发性硬化症患者的成本每年可能超过50,000美元。因此，即使是一项简单的验证性测试，也将对医疗体系产生重大的财务好处。能否根据全血中特定疾病的mRNAs表达水平来构建能够提供临床有用信息的疾病分类器，这一问题已经研究了十多年。研究实验室已经确定了许多疾病特异的基因表达特征。其中一些甚至已经发展成为商业上可行的诊断测试，特别是肠易激综合征、纤维肌痛和系统性硬化症。长非编码RNA(LncRNA)是最近发现的一种调节性RNA分子，它不编码蛋白质，但影响着大量的生物过程。在脊椎动物中，lncRNA基因的数量远远超过蛋白质编码基因的数量。也有人认为，lncRNAs导致了脊椎动物和无脊椎动物之间更大的生物复杂性。这些lncRNAs还表现出比mRNAs更大的细胞类型特异性表达模式。与其他生物体相比，人类还会患上更复杂的疾病。因此，我们在初步研究中提供的数据支持这样的概念，即与疾病相关的lncRNA在表达上的差异比与疾病相关的mRNA要大得多。在这个应用中，我们建议探索这样一个假设，即lncRNAs比mRNAs是更好的人类疾病生物标记物。在这里，我们将把MS作为一种疾病类别，并鉴定与MS相关的差异表达的lncRNAs。关于lncRNAs在人类自身免疫性疾病中的研究还处于起步阶段，而将lncRNAs作为自身免疫性疾病的生物标记物的探索还没有被解决。我们提出了以下具体目标：识别在MS中差异表达的注释和新的lncRNAs，并评估它们作为生物标志物的功能，以区分MS患者与健康受试者和其他神经系统疾病患者。

 DESCRIPTION (provided by applicant): Diagnosis of multiple sclerosis [MS] rests on clinical symptoms and examinations supported by appropriate magnetic resonance imaging findings or other laboratory tests such as oligoclonal bands in cerebrospinal fluid and evoked potential testing. Clinically isolated syndrome (CIS) is a first neurologic episode lasting at least 24 hours possibly caused by focal inflammation or demyelination. Approximately 10,000-15,000 new diagnoses of MS are made in the United States each year. Approximately 2-3 times that number experience a CIS each year indicating that a far greater number of subjects experience a CIS than develop MS. Costs to healthcare of determining if a subject with a CIS will develop MS are significant. Furthermore, misdiagnosis of MS produces a huge cost burden on our healthcare system as it is a frequent event and with the rising cost of newer as well as older therapies, the cost of managing a person with MS can exceed $50,000 per year. Thus, even a simple confirmatory test would be of significant financial benefit to the healthcare system. The question of whether or not disease classifiers capable of providing clinically useful information could be built based upon disease-specific expression levels of mRNAs in whole blood has been a subject of research for greater than ten years. Many disease-specific gene expression signatures have been identified in the research lab. A few of these have even progressed into commercially viable diagnostic tests, notably for irritable bowel syndrome, fibromyalgia, and systemic sclerosis. Long non-coding RNAs (lncRNA) are recently discovered regulatory RNA molecules that do not code for proteins but influence a vast array of biological processes. In vertebrates, the number of lncRNA genes greatly exceeds the number of protein-coding genes. It is also thought that lncRNAs drive greater biologic complexity between vertebrates and invertebrates. These lncRNAs also show much greater cell-type specific expression patterns than mRNAs. Humans also develop many more complex diseases than other organisms. As such, our data presented in preliminary studies, support the notion that disease-associated lncRNAs exhibit far greater differences in expression than disease-associated mRNAs. In this application, we propose to explore the hypothesis that lncRNAs are better biomarkers of human disease than mRNAs. Here, we will focus on MS as a disease category and have identified MS associated differentially expressed lncRNAs. Study of lncRNAs in human autoimmune disease is in its infancy and exploration of lncRNAs as biomarkers of autoimmune disease has not been previously addressed. We propose the following specific aim: To identify annotated and novel lncRNAs differentially expressed in MS and assess their function as biomarkers to distinguish MS subjects from healthy subjects and subjects with other neurologic disorders.