Effects of miR-21 and miR-155 inhibition in SLE

miR-21 和 miR-155 抑制对 SLE 的影响

基本信息

批准号：
8634023
负责人：
MARIANTHI KIRIAKIDOU
金额：
$ 16.47万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-04-01 至 2015-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8634023
关键词：
Affect African American Age Antibodies Antibody Formation Antigen-Antibody Complex Antigen-Presenting Cells Apoptotic Autoantibodies Autoimmune Diseases Autoimmune Process Autoimmunity B-Lymphocytes Cell Death Cell Differentiation process Cell Lineage Cell Survival Cell physiology Cells Cessation of life Chronic Clinical Trials Complex DNA Data Dendritic Cells Deposition Developmental Process Disease Employee Strikes Environmental Risk Factor Excision Experimental Designs Failure Female Functional RNA Gene Expression General Population Genes Genetic Hispanics Human Hyperactive behavior Immune Tolerance Immune response Immune system Immunoglobulins Immunologics In Vitro Interferons Investigation Kidney Kidney Diseases Kidney Failure Link Lung Lung diseases Lupus Lupus Nephritis Lymphocyte Lymphocyte Function Methodology Methods MicroRNAs Modality Modeling Monoclonal Antibodies Multicenter Studies Mus Natural Immunity Nephritis Organ Organ failure Outcome Pathway interactions Patients Peripheral Plasma Cells Process Production RNA Race Regulation Replacement Therapy Reporting Research Rheumatoid Arthritis Risk Role Scleroderma Self Tolerance Severities Signal Pathway Signal Transduction Sjogren&apos s Syndrome Splenomegaly Susceptibility Gene Systemic Lupus Erythematosus T cell differentiation T-Cell Activation T-Lymphocyte Therapeutic Therapeutic Intervention Time Tissues Translations Woman adaptive immunity belimumab cohort ethnic minority population high risk human disease immunoregulation in vivo inhibitor/antagonist lupus prone mice macrophage male mortality mouse model novel novel therapeutics outcome forecast public health relevance reproductive research study sex systemic autoimmune disease therapeutic miRNA transcriptome sequencing young woman

项目摘要

DESCRIPTION (provided by applicant): Systemic lupus erythematosus (SLE, lupus) is a chronic systemic autoimmune disease characterized by production and survival of autoreactive antibodies and deposition of immune complexes to various tissues, leading to organ damage. Lupus affects primarily women of reproductive age, with a female to male ratio of 9:1. Mortality in SLE is increased compared to the general population. Higher risk of death is associated with female sex, younger age, shorter SLE duration and African American race. Studies have shown that SLE is more severe among African American, Hispanic and women of other ethnic minorities. Over the last two decades, lupus mortality rates increased by 67.8% among African American women. Results of studies have suggested that this may be related to worse renal involvement and outcome in African American patients. Renal and other severe SLE manifestations respond poorly to current therapeutic modalities and often require replacement therapy. microRNAs (miRNAs) regulate a plethora of normal cellular and developmental processes and their function is linked to human disease. miRNAs are aberrantly expressed in human and mouse SLE, however their specific role in the immune response in lupus is not well understood. We study the function of miRNAs in SLE; our general hypothesis is that several miRNAs contribute to the disordered immunoregulation in lupus. Our long-term objective is to characterize and interfere with miRNA-regulated pathways common in mouse and human SLE and to investigate synthetic miRNA inhibitors as putative novel therapeutic direction in lupus. Our preliminary studies showed that LNA antimiRs efficiently antagonize endogenous miRNAs in peripheral lymphocytes in vivo and that LNA miR-21 inhibition ameliorates autoimmune manifestations in B6.Sle123. We will employ the same novel methodology for our in vivo and in vitro studies, to characterize the function of miR-21 and miR-155 in the immune system in lupus. In vivo studies in Aim I will inform us on role of miR-21 and miR-155 on autoantibody production, lymphocyte function and severe end-organ manifestations on genetic SLE models. In studies of inducible models we will examine the effect of selective miRNA inhibition targeting pathogenic, parental cells. We will investigate putative synergistic effect of miR-21 and miR- 155 and we will identify their targets in cells of the immune system. Experiments in Aim II will inform us on the role of miR-21 and miR-155 on T cell activation in lupus. In parallel, we will clone and sequence biologically relevant targets of all miRNAs in mouse SLE B and T lymphocytes, dendritic cells and macrophages, by employing two novel high throughput methods, HITS-CLIP and RNA seq. To our knowledge HITS-CLIP has not been previously performed in SLE and the combined results of HITS-CLIP and RNAseq will offer a panoramic view of all genes directly regulated by miRNAs in cells of the immune system in mouse lupus.

描述（由申请人提供）：全身性红斑狼疮（SLE，狼疮）是一种慢性全身自身免疫性疾病，其特征是自动反应性抗体的产生和存活以及对各种组织的免疫复合物的沉积，导致器官损害。狼疮主要影响生殖年龄的女性，女性与男性比例为9：1。与普通人群相比，SLE中的死亡率增加。较高的死亡风险与女性，年轻年龄，较短的SLE持续时间和非裔美国人种族有关。研究表明，在非裔美国人，西班牙裔和其他少数民族的妇女中，SLE更为严重。在过去的二十年中，非裔美国妇女的狼疮死亡率增加了67.8％。研究结果表明，这可能与非裔美国人患者的肾脏受累和结果较差有关。肾脏和其他严重的SLE表现对当前的治疗方式反应较差，通常需要替代疗法。 MicroRNA（miRNA）调节了许多正常的细胞和发育过程及其功能与人类疾病有关。 miRNA在人和小鼠SLE中异常表达，但是它们在狼疮中的免疫反应中的特定作用尚不清楚。我们研究miRNA在SLE中的功能；我们的总体假设是，几种miRNA有助于狼疮中的免疫调节。我们的长期目标是表征和干扰小鼠和人SLE中常见的miRNA调节途径，并研究合成miRNA抑制剂作为狼疮中假定的新型治疗方向。我们的初步研究表明，LNA抗杀菌剂在体内有效拮抗内源性miRNA，体内淋巴细胞中的内源性miRNA，而LNA miR-21抑制作用可以改善B6.SLE123中的自身免疫性表现。我们将使用相同的新方法来进行体内和体外研究，以表征miR-21和miR-155在狼疮中免疫系统中的功能。在AIM中，我将向我们告知我们MiR-21和miR-155在遗传SLE模型上的自身抗体产生，淋巴细胞功能和严重的终极出现表现方面的作用。在诱导模型的研究中，我们将研究靶向致病性，亲本细胞的选择性miRNA抑制作用。我们将研究miR-21和miR-155的假定协同作用，并将确定它们在免疫系统细胞中的靶标。 AIM II的实验将告知我们对miR-21和miR-155在狼疮中T细胞激活中的作用。同时，我们将通过采用两种新型的高吞吐量方法，即hits-clip和rna seq，将所有miRNA和T淋巴细胞，树突状细胞和巨噬细胞中所有miRNA的生物学相关靶标克隆和序列与生物学相关的靶标。据我们所知，hits-clip以前尚未在SLE中进行，hits-clip和rnaseq的综合结果将提供所有由miRNA直接调节的基因的全景视图，而小鼠狼疮中免疫系统细胞中则具有全景。