Identification of MicroRNA and Proteomics in immune cells and plasma in ALS

ALS 免疫细胞和血浆中的 MicroRNA 和蛋白质组学鉴定

• 批准号: 9303032
• 负责人: James Dale Berry
• 金额: $ 28.4万
• 依托单位: BRIGHAM AND WOMEN'S HOSPITAL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9303032
• 关键词: Ablation; Address; Amyotrophic Lateral Sclerosis; Animal Model; Anti-Inflammatory Agents; Anti-inflammatory; Applications Grants; Attention; Biological; Biological Markers; Blood; C9ORF72; CD14 gene; Cells; Clinical; Clinical Trials; Collaborations; Collection; Complex; Data; Data Analyses; Development; Dimensions; Disease; Disease Marker; Disease Progression; Drug Kinetics; Early Diagnosis; Event; Exhibits; FCGR3B gene; Frontotemporal Dementia; Functional disorder; Gene Expression Profile; Gene Mutation; Genes; Genetic; Genetic Transcription; Human; Immune; Immune System Diseases; Immune Targeting; Immune system; Immunologic Markers; Individual; Inflammatory; Investigation; Lead; Link; Longitudinal Studies; Longitudinal cohort; MicroRNAs; Microglia; Molecular; Monitor; Mus; Nerve Degeneration; Neurodegenerative Disorders; Onset of illness; Pathway interactions; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Pharmacodynamics; Phenotype; Plasma; Play; Process; Prognostic Marker; Proteins; Proteome; Proteomics; Reporting; Research; Research Design; Role; Sampling; Series; Spinal Cord; Stratification; Study Subject; Technology; Testing; Therapeutic; Time; Translations; Validation; Work; adaptive immune response; base; biomarker discovery; cohort; comparative; design; diagnostic biomarker; experimental study; follow-up; human disease; immune activation; immunoregulation; improved; inhibitor/antagonist; macrophage; monocyte; mouse model; neuroinflammation; new therapeutic target; potential biomarker; prospective; protein expression; proteomic signature; success; superoxide dismutase 1; transcriptome sequencing; treatment effect; treatment response

Project Summary The exact pathogenetic process that triggers neurodegeneration in ALS is currently unknown, but it is likely to be multifactorial, as for other neurodegenerative diseases. Recently, growing attention has been focused on events related to innate and adaptive immune responses, and there is increasing evidence of a significant involvement of inflammatory and immune pathways in the disease. However, their exact cellular identity, molecular and functional phenotypes, and their protective or detrimental roles in ALS progression are poorly understood. We previously found that both peripheral Ly6CHi monocytes in SOD1 mice and their analogous CD14+/CD16– monocytes from ALS patients express proinflammatory profiles. These studies lead us to begin a series of investigations to define markers of disease onset and progression in ALS. We started a prospective, longitudinal study collecting detailed clinical information, peripheral blood mononuclear cells (PBMCs) and plasma from people with ALS. Two cohorts of ALS subjects, sporadic (sALS) and familial (fALS), are followed up in time, from early until the late stages of the disease. The proposed project will identify the micro-RNA and proteomic signatures in blood-derived inflammatory monocytes and plasma in ALS. In Aim 1, we will investigate miRNA and proteomic changes in blood CD14+/CD16– monocytes and plasma from the onset and during disease progression of sALS and fALS (with SOD1 or C9orf72 gene mutations). The Aim design allows a comparative analysis of miRNA and protein expression in multiple dimensions utilizing 1) small RNA-seq to compare temporal changes of miRNAs expression within the ALS and healthy controls; 2) correlated clinical information in the variability over the time course; and 3) Integrated network data analysis between miRNA and proteomics. We leverage our unique longitudinal collection of sALS and fALS for which we have multipoint blood draws during their disease progression In Aim 2, we will characterize and validate the main hits in an independent validation cohort of ALS subjects. Acknowledging that the biomarker discovery in any field suffers from lack of replication, we believe that replication of our findings in an independent cohort is of highest importance. The independent replication, along with the validation of the main hits using different technologies will identify only robust potential biomarkers to further test for clinical utility.

项目摘要 引发ALS神经变性的确切发病过程目前尚不清楚，但它很可能 是多因素的，如其他神经退行性疾病。最近，越来越多的注意力集中在 与先天性和适应性免疫反应有关的事件，越来越多的证据表明， 炎症和免疫途径参与疾病。然而，它们的确切细胞身份， 分子和功能表型，以及它们在ALS进展中的保护或有害作用很差， 明白我们以前发现，SOD 1小鼠外周血Ly 6CHi单核细胞及其类似物 来自ALS患者的CD 14 +/CD 16-单核细胞表达促炎性特征。这些研究使我们开始 一系列研究来确定ALS中疾病发作和进展的标志物。我们开始了一个前瞻性的， 纵向研究收集详细的临床信息，外周血单核细胞（PBMC）和 从肌萎缩侧索硬化症患者身上提取的血浆跟踪两组ALS受试者，散发性（sALS）和家族性（fALS）， 从疾病的早期到晚期拟议的项目将确定微RNA， ALS患者血液来源的炎性单核细胞和血浆中的蛋白质组特征。 在目标1中，我们将研究血液CD 14 +/CD 16-单核细胞中的miRNA和蛋白质组学变化， 从sALS和fALS（具有SOD 1或C9 orf 72基因）的发病和疾病进展期间的血浆 突变）。Aim设计允许对多个细胞中的miRNA和蛋白质表达进行比较分析。 使用1）小RNA-seq比较ALS内miRNA表达的时间变化， 健康对照; 2）随时间变化的相关临床信息;和3）整合 miRNA和蛋白质组学之间的网络数据分析。我们利用我们独特的sALS纵向系列 以及在疾病进展期间进行多点抽血的fALS 在目标2中，我们将在ALS的独立验证队列中描述和验证主要命中 科目承认生物标志物的发现在任何领域都缺乏复制，我们相信， 在一个独立的队列中复制我们的发现是最重要的。独立复制， 沿着使用不同技术的主要命中的验证将仅识别稳健的潜力 生物标志物以进一步测试临床效用。