Circulating Non-coding RNAs as Biomarkers of Inclusion Body Myositis

循环非编码 RNA 作为包涵体肌炎的生物标志物

• 批准号: 8893583
• 负责人: James William Mandell
• 金额: $ 20.86万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-05-12 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8893583
• 关键词: Adrenal Cortex Hormones; Adverse effects; Affect; American; Anatomy; Autoantibodies; Basic Science; Biochemistry; Biological Markers; Biopsy; Blood; Blood Circulation; Body Fluids; Cells; Classification; Clinical; Clinical assessments; Complex; Connective Tissue Diseases; Creatine Kinase; Data; Dermatomyositis; Diagnosis; Disease; Disease Progression; Evolution; Explosion; Extracellular Space; FDA approved; Gold; Heterogeneity; Human; Idiopathic Inflammatory Myopathies; Immune; Inclusion Body Myositis; Injury; Institution; Laboratories; Measurement; Measures; Membrane; Metabolic; Methods; MicroRNAs; Molecular; Molecular Genetics; Molecular Profiling; Monitor; Morbidity - disease rate; Muscle; Myocardium; Myopathy; Myositis; Natural regeneration; Operative Surgical Procedures; Pathogenesis; Patient Monitoring; Patients; Pattern; Plasma; Prevalence; Protein Binding; RNA; Refractory; Research Personnel; Role; Sampling; Sensitivity and Specificity; Serum; Site; Skeletal Muscle; Special Hospitals; Steroids; Techniques; Testing; Therapeutic Clinical Trial; Therapeutic immunosuppression; Time; Tissues; Transcriptional Regulation; Untranslated RNA; Urine; Validation; Work; base; effective therapy; injury and repair; mortality; noninvasive diagnosis; novel; public health relevance; response; treatment response; verification and validation

 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).

 描述（由申请人提供）：特发性炎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），并且共同影响超过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无反应，具有严重的副作用。IBM诊断的金标准是肌肉活检，但该疾病的解剖学和时间异质性极大地限制了其敏感性和特异性。此外，活检是一种侵入性外科手术，不适合反复监测疾病进展和治疗反应。IBM没有可靠的血清生物标志物。基础研究的爆炸已经确定了关键的调控RNA，包括在肌肉分化和再生中起重要作用的microRNA和长链非编码RNA（lncRNA）。这些RNA被释放到细胞外空间，由于膜包裹和蛋白质结合，以非常稳定的形式到达血流和其他体液。由于肌肉占身体总质量的近一半，其RNA及其代谢产物为体液（包括血清和尿液）提供了很大的成分。我们的初步数据表明，肌肉特异性microRNA可以在人血清中检测到。该提案的目的是确定一小组RNA生物标志物，用于敏感，特异和非侵入性诊断包涵体肌炎。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性肌病的非编码RNA。目的2：验证和确认选择的非编码RNA作为包涵体肌炎的非侵入性血清和/或尿液生物标志物。目的1中包涵体肌炎的敏感和特异性组织生物标志物的发现将填补肌炎领域中关键的、未满足的需求，即这些标志物是否被发现是患者血清或尿液中的可靠生物标志物的难题（目的2）。