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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：
9544374
负责人：
Kong Chen
金额：
$ 38.75万
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：
2017
资助国家：
美国
起止时间：
2017-09-01 至 2018-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9544374
关键词：
Acute Adenoviruses Affect Bromodomain Bronchoscopy CXCL1 gene CXCL5 gene Cell Line Cells ChIP-seq Chromatin Chronic Clinical Clinical Trials Cystic Fibrosis Data Development Diagnosis Diagnostic Disease Drug Targeting Encyclopedia of DNA Elements Epigenetic Process Epithelial Epithelial Cells Epithelium Future Gene Expression Goals HDAC5 gene Histone Deacetylase Histone Deacetylation Human IL8 gene IL8RB gene Impairment In Vitro Infection 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 Protein Inhibition Pseudomonas Infections Pulmonary Pathology Regulation Research Role Signal Pathway Specificity T-Lymphocyte Tertiary Protein Structure Transcription Coactivator base chemokine chromatin immunoprecipitation chromatin remodeling clinical practice cystic fibrosis patients epigenetic regulation experimental study histone modification human disease improved in vivo inflammatory lung disease inhibitor/antagonist knock-down mouse model neutrophil novel overexpression receptor response targeted treatment transcriptome transcriptome sequencing

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）的主要肺部病理，与白细胞介素-17的产生有关。我们的长期目标是阐明 IL-17产生的调节，并分析了在IL-17产生过程中的下游嗜酸性反应。肺IL-17促进CXCR2配体的产生，包括CXCL5，其具有对中性粒细胞的趋化和活化功能，特别是在急性炎症应答初步数据表明，IL-17增强了这些基因的表达，趋化因子通过组蛋白修饰。虽然IL-17可以促进炎症通过稳定编码CXCR2配体的mRNA，该提案中描述的是一种新颖的，可能对治疗产生重大的临床影响。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在上皮中产生CXCR2配体通过抑制HDAC5和IL-17诱导的上皮CXCL5的可及性，肺部慢性嗜酸性炎症所必需的。在AIM1中，我们将确定上皮IL-17受体在调节最佳Cxc15表达中的作用和慢性炎症中的中性粒细胞募集。我们将使用条件性IL-17 R KO 在建立的模拟人类嗜肺性肺病的鼠模型中，在目的2，我们将确定IL-17诱导的CXCR2配体表达是否需要组蛋白去乙酰化酶HDAC5，从初步研究中鉴定。在AIM3中，我们将寻求使用破坏IL-17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是为了最大化靶向IL-17通路在慢性炎症中的临床益处，定义IL-17驱动趋化因子表达的表观遗传机制。这申请旨在通过以下方式改变当前的研究和临床实践范式：鉴定IL-17促进IL-17表达新的表观遗传调节机制 CF上皮中的嗜中性炎症。这些目标产生的结果可能不仅对CF，而且对其他嗜酸细胞也有深刻的翻译意义，炎性条件。