Expression and function of microRNA in autoimmune Sjogren's Syndrome

microRNA在自身免疫性干燥综合征中的表达和功能

• 批准号: 8100296
• 负责人: SEUNGHEE CHA
• 金额: $ 35.53万
• 依托单位: UNIVERSITY OF FLORIDA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8100296
• 关键词: 3' Untranslated Regions; Acids; Address; Affect; Age; American; Autoimmune Diseases; Autoimmune Process; Autoimmunity; Biological; Biological Assay; Biological Markers; Biopsy Specimen; Cell Line; Cells; Characteristics; Clinical; Complex; Computer Simulation; Control Groups; Data; Development; Diagnosis; Diagnostic; Disease; Disease Marker; Epigenetic Process; Exhibits; Exocrine Glands; Female; Functional RNA; Functional disorder; Gene Targeting; Genes; Goals; Human; Immune; Immune response; In Situ Hybridization; In Vitro; Individual; Inflammation; Inflammatory; Lacrimal gland structure; Luciferases; MicroRNAs; Natural Immunity; Nature; Nuclear; Onset of illness; Pathogenesis; Patients; Peripheral Blood Mononuclear Cell; Phagocytosis; Play; Prevention; Process; Production; Quality of life; RNA Interference; Recruitment Activity; Regulation; Research; Research Design; Research Proposals; Rheumatoid Arthritis; Role; Salivary Glands; Screening Result; Screening procedure; Sjogren' s Syndrome; Specificity; Staging; Stimulus; Syndrome; System; Systemic Lupus Erythematosus; Testing; Therapeutic; Therapeutic Intervention; Time; Tissues; Transfection; Up-Regulation; Viral; Xerostomia; cytokine; eye dryness; human old age (65+); improved; in vitro testing; in vivo; inhibitor/antagonist; insight; monocyte; mouse model; novel; public health relevance; research study; response; tool

DESCRIPTION (provided by applicant): Autoimmune Sj"gren's syndrome (SjS) targets the exocrine glands, such as the salivary and lacrimal glands, of mostly female individuals, leading to severe secretory dysfunction and its complications. To date, SjS- specific diagnostics and therapeutics have not been available due to complexity of SjS disease pathogenesis. MicroRNAs (miRNAs) have been recognized as an important class of non-coding RNAs that are involved in a variety of biological, pathological, and immunological processes. Our latest findings on altered miR-146a and- 155 expression in peripheral blood mononuclear cells (PBMC) or monocytes of primary SjS (pSjS) patients in comparison with healthy controls indicate that miRNAs may play a critical role in autoimmune initiation and progression of SjS. The data were further supported by the findings in the salivary glands and PBMC of our pSjS-prone C57BL/6.NOD-Aec1Aec2 mouse model, where up-regulation of those miRNAs was observed from an early age on. Over-expression of miR-146a in human monocyte cell line (THP-1) was able to alter innate immune responses such as phagocytosis and pro-inflammatory cytokine production in our preliminary study in vitro. We now propose studies designed to test our hypotheses that miR-146a and miR-155 are vital to prolong inflammatory processes by altering innate immune response and that pSjS-specific miRNAs especially involved in innate immunity can be differentially expressed (potentially even prior to disease onset resulting in persistent inflammation). In Aim 1 of this project, we will investigate consequences of altered miR-146a and/or miR-155 by utilizing miRNA mimics and inhibitors transfected into THP-1 cells followed by functional assays. Altered functions will also be tested in primary cultured monocytes from pSjS patients. This aim is to determine if epigenetic regulation of immune genes by miRNAs are critical in altering immunological processes in SjS. In Aim 2, we will begin to profile a complex network of miRNAs involved in pSiS by utilizing a miRNA microarray approach. Here we will test our hypothesis that miRNA profiles that are specific for human pSjS are identifiable. Furthermore, we will continue to identify in Aim 2 target genes of differentially expressed miRNAs and perform functional assays established in Aim 1 to screen their involvement in innate immune responses. We envision that these experiments will identify novel miRNAs in pSjS and regulatory functions of identified miRNAs in abnormal immune regulation of SjS and may ultimately be amenable to development of biomarkers and therapeutic intervention. PUBLIC HEALTH RELEVANCE: Sj"gren's syndrome (SjS) affects 4 million Americans, resulting in dry mouth and dry eye condition in patients. Our research proposal to identify SjS-specific profiles would advance diagnostics and therapeutics in the field and improve quality of life in those affected with the disease.

描述（由申请人提供）：自身免疫SJ“ Gren's综合征（SJS）针对的是大多数女性个体的外分泌腺，例如唾液和泪腺，唾液和泪腺，导致严重的分泌功能障碍及其并发症。迄今为止，由于SJS-特定的诊断和治疗性的疾病，SJS尚未确定SJS的疾病。作为一类重要的非编码RNA，我们在各种生物学，病理学和免疫过程中都有有关MiR-146A的最新发现，并且在周围血液单核细胞（PBMC）中的表达（PBMC）或单核细胞与健康对照组相比，Mirna的起作用可能会播放我们的PSJS-易于c57BL/6.NOD-AEC1AEC2小鼠模型的发现中的发现进一步支持了数据，其中从早期就观察到了这些miRNA的上调。在人类单核细胞系（THP-1）中，miR-146a的过表达能够改变先天免疫反应，例如吞噬作用和促炎性细胞因子的产生，在我们的初步研究中。现在，我们提出的研究旨在测试我们的假设，即miR-146a和miR-155通过改变先天免疫反应而对延长炎症过程至关重要，并且可以差异地表达PSJS特异性的miRNA，尤其是与先天免疫相关的miRNA（甚至可以在持续性炎症引起的疾病发作之前，也可能会差异化）。在该项目的AIM 1中，我们将通过利用miRNA模拟物和转染到THP-1细胞的抑制剂，然后进行功能测定，研究改变miR-146a和/或miR-155改变的后果。在PSJS患者的原发性培养单核细胞中也将测试变化的功能。该目的是确定miRNA对免疫基因的表观遗传调节对于改变SJ的免疫过程至关重要。在AIM 2中，我们将通过使用miRNA微阵列方法开始介绍涉及PSI的miRNA网络。在这里，我们将测试我们的假设，即针对人PSJ的miRNA谱是可识别的。此外，我们将继续在AIM 2中识别差异表达的miRNA的目标基因，并执行AIM 1中确定的功能测定，以筛选其参与先天免疫反应。我们设想这些实验将鉴定PSJ中的新型miRNA和SJS异常免疫调节中鉴定的miRNA的调节功能，并且最终可能与生物标志物和治疗干预的发展相吻合。 公共卫生相关性：SJ“ Gren's综合征（SJ）会影响400万美国人，导致患者的口干和干眼病。我们的研究建议识别SJS特异性概况将提高该领域的诊断和治疗疗法，并改善患有疾病患者的生活质量。