DNA-Based Biomarkers for Multiple Sclerosis

基于 DNA 的多发性硬化症生物标志物

• 批准号: 7331179
• 负责人: VICTOR V LEVENSON
• 金额: $ 21.1万
• 依托单位: NORTHWESTERN UNIVERSITY AT CHICAGO
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-07-15 至 2008-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7331179
• 关键词: Address; Affect; Age; Agreement; Autoantibodies; Biological Assay; Biological Markers; Blood; Blood - brain barrier anatomy; Blood Circulation; Cells; Central Nervous System Diseases; Cerebrospinal Fluid; Cessation of life; Chronic; Clinical; Clinical Trials; Condition; DNA; DNA Methylation; DNA Modification Process; Data; Detection; Development; Diagnosis; Diagnostic; Disease; Disease Progression; Disease remission; Drug Delivery Systems; Epigenetic Process; Evaluation; Evoked Potentials; Fingers; Foundations; Future; Gene Expression; Genes; Genetic; Genetic Polymorphism; Genomics; Histocompatibility Antigens Class II; Home environment; Inflammation; Inflammatory; Invasive; Laboratories; Lead; Lesion; Link; Magnetic Resonance Imaging; Malignant Neoplasms; Methylation; Migraine; Modification; Molecular; Monitor; Multiple Sclerosis; Mutation; Myelin Proteins; Nature; Nerve Degeneration; Neuraxis; Neurodegenerative Disorders; Onset of illness; Outcome; Patients; Pattern; Physiological; Plasma; Predisposition; Procedures; Process; Prospective Studies; Relapsing-Remitting Multiple Sclerosis; Reporting; Role; Sampling; Secondary Progressive Multiple Sclerosis; Selection for Treatments; Signal Transduction; Specimen; Speed; Staging; Statistically Significant; Stroke; Surrogate Endpoint; Symptoms; Syndrome; Systemic Lupus Erythematosus; Techniques; Testing; Time; Treatment Efficacy; base; clinical Diagnosis; disability; disorder control; genetic association; novel; promoter; prospective; research study; response; sample collection; sex; success; therapy development; transmission process; tumor

DESCRIPTION (provided by applicant): Multiple sclerosis (MS) is a chronic, inflammatory neurodegenerative disease that affects the central nervous system and may lead to severe disability within 10-15 years. MS is diagnosed by clinical symptoms and presence of inflammation detected by magnetic resonance imaging. Other diseases present with similar symptoms, so diagnosis of MS is challenging. The lack of clear and objective biomarkers for diagnosis, monitoring, or prediction of outcomes complicates MS detection and treatment of MS patients. We propose to use a novel assay developed in our laboratory for analysis of DNA methylation to identify MS-specific changes of DNA methylation in multiple genes within each specimen, and to create a composite biomarker combining genes with the most diverse patterns of methylation. The blood-brain barrier is disrupted in MS patients, genomic DNA from dead cells is released into the bloodstream, so the assay can be based on cell-free circulating DNA. Specific Aims of the project are: (1) to establish a composite biomarker for detection of patients with relapsing-remitting MS in remission based on DNA methylation profile of cell-free circulating plasma DNA; (2) to establish a composite biomarker for detection of patients with relapsing-remitting MS during exacerbations based on DNA methylation profile of cell-free circulating plasma DNA, and to compare it with the biomarker established in Aim 1; (3) to compare DNA methylation profiles of patients with relapsing- remitting MS and secondary-progressive MS and to determine biomarkers specific for progression. The assay allows simultaneous detection of methylation in 56 gene promoters using DNA from 0.15 ml of plasma. The assay successfully detected MS-specific changes in DNA from plasma of MS patients. Completion of this project will produce a novel set of objective observer-independent biomarkers based on a fast, simple, and inexpensive procedure, and utilizing a simple, safe, and minimally invasive specimen collection. There are no reports on MS-specific DNA methylation, so this project will be the first to address this deficiency. The utility of cell-free circulating DNA for testing in MS has never been reported, so this project will be the first to use this opportunity. Consequently, other components of this project are without precedent: a biomarker for different forms of RR-MS, a biomarker for prediction of an attack, and a biomarker for disease progression to SP-MS will be developed for the first time. Multiple sclerosis (MS) is a chronic inflammatory disease of the central nervous system, which can lead to severe disability and death. Diagnosis of MS is difficult because initial stages of the disease do not have obvious symptoms or even any symptoms at all, and there are no objective markers specific for MS. In this project we will use a new technique developed in our laboratory to evaluate DNA modifications (methylation) in blood of MS patients with active MS (attack or exacerbation) and stable MS (remission). Completed project will provide the first objective biomarker based on MS-specific DNA methylation, which can be used for diagnosis of MS, for evaluation of treatments success, and for prediction of outcomes.

描述（由申请人提供）：多发性硬化症 (MS) 是一种慢性炎症性神经退行性疾病，会影响中枢神经系统，并可能在 10-15 年内导致严重残疾。 MS 通过临床症状和磁共振成像检测到炎症的存在来诊断。其他疾病也有类似的症状，因此多发性硬化症的诊断具有挑战性。由于缺乏用于诊断、监测或预测结果的清晰客观的生物标志物，使得多发性硬化症患者的检测和治疗变得复杂。我们建议使用我们实验室开发的一种新颖的检测方法来分析 DNA 甲基化，以识别每个样本内多个基因中 DNA 甲基化的 MS 特异性变化，并创建一个将具有最多样化甲基化模式的基因结合起来的复合生物标志物。 MS 患者的血脑屏障被破坏，死亡细胞的基因组 DNA 被释放到血流中，因此该检测可以基于无细胞循环 DNA。该项目的具体目标是：（1）基于无细胞循环血浆DNA的DNA甲基化谱，建立一种复合生物标志物，用于检测缓解期复发缓解型多发性硬化症患者； (2) 基于无细胞循环血浆 DNA 的 DNA 甲基化谱建立复合生物标志物，用于检测恶化期间复发缓解型多发性硬化症患者，并将其与目标 1 中建立的生物标志物进行比较； (3) 比较复发缓解型多发性硬化症和继发进展性多发性硬化症患者的 DNA 甲基化谱，并确定进展特异性的生物标志物。该测定可以使用 0.15 ml 血浆中的 DNA 同时检测 56 个基因启动子的甲基化。该检测成功检测了 MS 患者血浆中 DNA 的 MS 特异性变化。该项目的完成将基于快速、简单和廉价的程序，并利用简单、安全和微创的标本采集，产生一套新颖的、独立于观察者的客观生物标志物。目前还没有关于 MS 特异性 DNA 甲基化的报道，因此该项目将是第一个解决这一缺陷的项目。无细胞循环 DNA 在 MS 测试中的效用从未有过报道，因此该项目将是第一个利用这一机会的项目。因此，该项目的其他组成部分是史无前例的：将首次开发用于不同形式 RR-MS 的生物标志物、用于预测发作的生物标志物以及用于疾病进展到 SP-MS 的生物标志物。多发性硬化症（MS）是一种中枢神经系统慢性炎症性疾病，可导致严重残疾和死亡。 MS的诊断很困难，因为疾病的初始阶段没有明显的症状，甚至根本没有任何症状，并且没有针对MS的客观标志物。在这个项目中，我们将使用我们实验室开发的新技术来评估患有活动性多发性硬化症（发作或恶化）和稳定多发性硬化症（缓解）的多发性硬化症患者血液中的 DNA 修饰（甲基化）。已完成的项目将提供第一个基于 MS 特异性 DNA 甲基化的客观生物标志物，可用于诊断 MS、评估治疗成功和预测结果。