Epigenetic regulation of chemokines in lung inflammation

肺部炎症趋化因子的表观遗传调控

基本信息

批准号：
10237370
负责人：
Kong Chen
金额：
$ 39.06万
依托单位：
UNIVERSITY OF PITTSBURGH AT PITTSBURGH
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-09-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10237370
关键词：
Acute Adenoviruses BRD2 gene Bromodomain Bronchoscopy CXCL1 gene CXCL5 gene Cell Line Cells ChIP-seq Chromatin Chronic Clinical Clinical Trials Cystic Fibrosis Data Development Diagnosis Diagnostic Drug Targeting Encyclopedia of DNA Elements Epigenetic Process Epithelial Epithelial Cells Future Gene Expression Goals HDAC5 gene Histone Deacetylase Histone Deacetylation Human IL8 gene IL8RB gene Impairment In Vitro Inflammation Inflammatory Inflammatory Response Interleukin-17 Knockout Mice Ligands Link Lung Lung Inflammation Lung diseases Mediating Messenger RNA Modeling Mus Neutrophil Infiltration Pathogenesis Pathway interactions Pharmacology Production Pseudomonas Infections Pulmonary Pathology Regulation Research Role Signal Pathway Specificity T-Lymphocyte Tertiary Protein Structure Transcription Coactivator acute infection airway epithelium base bronchial epithelium chemokine chromatin immunoprecipitation chromatin remodeling chronic inflammatory disease chronic inflammatory lung disease clinical practice cystic fibrosis patients epigenetic regulation experimental study histone modification human disease improved in vivo inhibitor/antagonist knock-down mouse model neutrophil novel overexpression receptor response single-cell RNA sequencing targeted treatment transcriptome

项目摘要

Neutrophilic inflammation is the dominant lung pathology in cystic fibrosis (CF) which is associated with elevated Interleukin-17 production. Our long-term goal is to elucidate the regulation of IL-17 production and dissect the downstream neutrophilic responses in the lungs. IL-17 promotes the production of CXCR2 ligands including CXCL5, which has chemotactic and activating functions on neutrophil especially during acute inflammatory responses. Preliminary data indicate that IL-17 augments the expression of these chemokines through histone modification. Although IL-17 can promote inflammation through stabilizing mRNAs encoding CXCR2 ligands, the epigenetic regulation described in this proposal is novel and could have significant clinical impact on treatment and diagnosis of chronic inflammatory diseases. We hypothesize that IL-17 enhances CXCR2 ligands production in the epithelium through increasing chromatin accessibility by repressing HDAC5 and that IL-17 induced epithelial CXCL5 is required for chronic neutrophilic inflammation in the lungs. In Aim1, we will determine the roles of epithelial IL-17 receptors in regulating optimal Cxcl5 expression and neutrophil recruitment in chronic inflammation. We will use conditional IL-17R KO mice in established murine models mimicking neutrophilic lung disease in humans. In Aim2, we will determine if the IL-17 induced expression of CXCR2 ligands requires histone deacetylase HDAC5, identified from the preliminary studies. In Aim3, we will seek to inhibit IL-17 mediated lung inflammation in vivo using compounds that disrupt chromatin remodeling and gene expression. The long-term goal of this research will be to maximize the clinical benefit of targeting the IL-17 pathway in chronic inflammation by defining the epigenetic mechanism of IL-17 driven expression of chemokines. This application seeks to shift current research and clinical practice paradigms by identification of a novel epigenetic regulatory mechanism by which IL-17 promotes neutrophilc inflammation in CF epithelium. The findings generated from these aims may have profound translational implications not only to CF but also to other neutrophilic inflammatory conditions.

中性粒细胞炎症是囊性纤维化（CF）中的主要肺病理学与白介素17的产量升高有关。我们的长期目标是阐明调节IL-17产生并剖析下游中性粒细胞反应肺。 IL-17促进CXCR2配体的产生，包括CXCL5 趋化性和激活功能对中性粒细胞，尤其是在急性炎症期间回答。初步数据表明IL-17增加了这些的表达通过组蛋白修饰趋化因子。尽管IL-17可以促进炎症通过稳定编码CXCR2配体的mRNA，表观遗传调节该提案中描述的是新颖的，可能对治疗产生重大临床影响和慢性炎症性疾病的诊断。我们假设IL-17增强了通过增加染色质，上皮中的CXCR2配体产生通过抑制HDAC5的可访问性，而IL-17诱导的上皮CXCL5为肺部慢性中性粒细胞炎症所必需的。在AIM1中，我们将确定上皮IL-17受体在调节最佳CXCL5表达中的作用和中性粒细胞在慢性炎症中的募集。我们将使用有条件的IL-17R KO 在既定的鼠模型中模仿了人类中性粒细胞性肺部疾病的小鼠。在 AIM2，我们将确定IL-17诱导的CXCR2配体的表达是否需要从初步研究中确定的组蛋白脱乙酰基酶HDAC5。在AIM3中，我们将寻求使用破坏的化合物在体内抑制IL-17介导的肺部炎症染色质重塑和基因表达。这项研究的长期目标将是为了最大化靶向慢性炎症中IL-17途径的临床益处定义IL-17驱动趋化因子表达的表观遗传机理。这申请旨在通过 IL-17促进的新型表观遗传调节机制的鉴定 CF上皮中嗜中性粒细胞炎症。这些目标产生的发现可能对CF具有深远的翻译意义，而且对其他中性粒细胞具有炎症条件。