Circulating Non-coding RNAs as Biomarkers of Inclusion Body Myositis

 描述(申请人提供)：特发性炎症性肌病包括多发性肌炎(PM)、皮肌炎(DM)、坏死性肌炎(NM)和包涵体肌炎(IBM)，总共影响超过75,000名美国人。IBM的正确诊断尤其重要，因为这种疾病对免疫抑制疗法没有反应，免疫抑制疗法有严重的副作用。IBM诊断的金标准是肌肉活检，但这种疾病的解剖和时间异质性极大地限制了其敏感性和特异性。此外，活检是一种侵入性的外科手术，不适合重复监测疾病的演变和治疗反应。IBM目前还没有可靠的血清生物标志物。大量的基础研究已经确定了关键的调控RNA，包括在肌肉分化和再生中起关键作用的微小RNA和长非编码RNA(LncRNAs)。由于膜的包裹和蛋白质的结合，这些RNA被释放到细胞外空间，以非常稳定的形式到达血液和其他体液。由于肌肉占身体总质量的近一半，其RNA及其代谢产物为包括血清和尿液在内的体液贡献了很大一部分。我们的初步数据表明，可以在人血清中检测到肌肉特异的microRNAs。该提案的目的是确定一小部分RNA生物标记物，用于包涵体肌炎的敏感、特异和非侵入性诊断。这将通过完成两个具体目标来实现。目的1：发现和验证区分包涵体肌炎和其他特发性炎症性肌病的非编码RNA。目的2：验证和验证筛选的非编码RNA作为包涵体肌炎的非侵袭性血清和/或尿液生物标志物。在Aim 1中发现包涵体肌炎的敏感和特定的组织生物标记物将填补肌炎领域中一个关键的、尚未得到满足的需求，无论这些标记物是否被发现是患者血清或尿液中的可靠生物标记物(Aim 2)。

 DESCRIPTION (provided by applicant): The idiopathic inflammatory myopathies include polymyositis (PM), dermatomyositis (DM), necrotizing myositis (NM) and inclusion body myositis (IBM), and together affect greater than 75,000 Americans. The correct diagnosis of IBM is especially important, since this disorder is unresponsive to immunosuppressive therapies, which have serious side effects. The gold standard for IBM diagnosis is muscle biopsy, but anatomic and temporal heterogeneity of the disorder greatly limits its sensitivity and specificity. Moreover biopsy is an invasive surgical procedure, and not appropriate for repeated monitoring of disease evolution and treatment response. There are no reliable serum biomarkers for IBM. An explosion of basic research has identified key regulatory RNAs, including microRNAs and long non-coding RNAs (lncRNAs) that have essential roles in muscle differentiation and regeneration. These RNAs are released into the extracellular space, reaching the bloodstream and other body fluids in very stable forms, due to both membrane encapsulation and protein binding. Because muscle makes up nearly half of the total body mass, its RNAs and their metabolic products contribute a large component to body fluids, including serum and urine. Our preliminary data indicates that muscle- specific microRNAs can be detected in human serum. The objective of the proposal is to identify a small panel of RNA biomarkers for the sensitive, specific and non-invasive diagnosis of inclusion body myositis. This will be accomplished by the completion of two specific aims. Aim 1: Discovery and validation of non-coding RNAs that distinguish inclusion body myositis from other idiopathic inflammatory myopathies. Aim 2: Verification and validation of selected non-coding RNAs as non-invasive serum and/or urine biomarkers of inclusion body myositis. Discovery of sensitive and specific tissue biomarkers of inclusion body myositis in Aim 1 would fill a critical, unmet need in the myositis field, regardles of whether these markers are found to be reliable biomarkers in patient serum or urine (Aim 2).