Gene-environment interaction pathways in rheumatoid arthritis

类风湿性关节炎的基因-环境相互作用途径

基本信息

批准号：
10380826
负责人：
Joseph Holoshitz
金额：
$ 52.89万
依托单位：
UNIVERSITY OF MICHIGAN AT ANN ARBOR
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-09 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10380826
关键词：
ATAC-seq Address Affect Affinity Agonist Algorithms Alleles Arthritis Aryl Hydrocarbon Receptor Bioinformatics Biological Assay Cells ChIP-seq Chromatin Code Congenic Mice Data Development Dioxins Disease Disease susceptibility Dose Environmental Pollutants Environmental Risk Factor Epidemiology Epitopes Event Experimental Models Exposure to Future Genes Genetic Genetic Markers Genetic Predisposition to Disease Genetic Risk HLA-DRB1 High-Throughput Nucleotide Sequencing Human Human Cell Line IL17 gene In Vitro Lead Ligands Maps Mediating Methods Mus NF-kappa B Osteoclasts Pathogenicity Pathway Analysis Pathway interactions Patients Physiological Prevalence Protocols documentation Public Health Quantitative Reverse Transcriptase PCR Research Research Project Grants Rheumatoid Arthritis Risk Role Severities Severity of illness System Tobacco smoke Transcriptional Activation Transgenic Mice Transposase Urban Population Validation Work base bone disorder risk draining lymph node gene environment interaction genetic risk factor genome-wide in vivo interest joint inflammation macrophage monocyte new therapeutic target peripheral blood receptor synergism tobacco smoke exposure transcription factor transcriptome sequencing transcriptomics translational study

项目摘要

ABSTRACT Shared epitope (SE)-coding HLA-DRB1 alleles confer the single strongest genetic risk for severe RA. In addition to genetic predisposition, exposure to environmental pollutants, such as dioxin-like compounds, and tobacco smoke strongly affect RA risk and severity. Furthermore, interactions between SE and tobacco smoke exposure has been shown to increase the risk for RA in a multiplicative, dose-dependent fashion. The mechanistic basis of this epidemiologically observed gene-environment interaction is unknown. We have recently uncovered an NF-kB-mediated crosstalk between the SE and aryl hydrocarbon receptor (AhR) pathways that lead to synergistic effects on osteoclast differentiation and Th17 polarization in vitro. Administration of AhR pathway agonists to transgenic mice carrying human SE-coding alleles resulted in a robust increase in arthritis severity, bone destruction and overabundance of osteoclasts and IL17-expressing cells in the inflamed joints and draining lymph nodes of arthritic mice. Thus, we have uncovered a previously unrecognized mechanism of gene-environment interaction. The studies proposed here will focused on detailed characterization of the newly uncovered synergism by defining the transcriptomic effects of the SE ligand, AhR agonists, and their combination. The physiologic relevance of the findings will be corroborated in in vivo mouse systems, as well as by human translational studies. The proposed research will have the following specific aims:  To identify and map the synergistic pathways using an RNA-seq approach  To determine the effect of the interaction on chromatin accessibility and validate transcription factor activation  To validate interacting pathways in mice exposed to AhR agonists  To determine pathway interactions in human cell lines and primary cells When successfully completed, the proposed project will have identified new pathogenic mechanisms and disease risk and severity markers in RA. Such findings will open the door to identification of new therapeutic targets that could be pursued in future research projects.

抽象的共享发作（SE） - 编码HLA-DRB1等位基因会议会议严重RA的单个强遗传风险。在除遗传易感性，暴露于环境污染物（例如二恶英化合物）和烟草烟雾强烈影响RA的风险和严重程度。此外，SE和烟草烟之间的相互作用已显示暴露会增加以乘法，剂量依赖性方式增加RA的风险。这这种流行病学观察到的基因 - 环境相互作用的机械基础尚不清楚。我们最近发现了SE和芳基烃接收器之间的NF-KB介导的串扰（AHR）在体外对破骨细胞分化和Th17极化产生协同作用的途径。给携带人类SE编码等位基因的转基因小鼠的AHR途径激动剂的给药导致关节炎的严重程度，骨破坏和破骨细胞的过度增加和表达IL17 关节发炎的细胞和淋巴结的淋巴结。那，我们已经发现了以前的基因环境相互作用的未识别机制。此处提出的研究将集中在详细的表征新发现的协同作用的详细表征定义了Se配体，AHR激动剂的转录组及其组合。生理学这些发现的相关性将在体内小鼠系统中以及人类翻译中得到证实研究。拟议的研究将具有以下具体目标： 使用RNA-seq方法识别和映射协同途径 确定相互作用对染色质可及性和验证转录因子的影响激活 验证暴露于AHR激动剂的小鼠中的相互作用途径 确定人类细胞系和原代细胞中的途径相互作用成功完成后，拟议的项目将确定新的致病机制，并 RA中的疾病风险和严重性标记。这样的发现将打开识别新的大门可以在未来的研究项目中追求的治疗靶标。