Epigenetic regulation of chemokines in lung inflammation

肺部炎症趋化因子的表观遗传调控

• 批准号: 9982393
• 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
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-01 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9982393
• 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; Epithelium; 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; 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; single-cell RNA sequencing; targeted treatment; transcriptome

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。 与白介素17的产生增加有关。我们的长期目标是澄清 白细胞介素17产生的调节及下游中性粒细胞反应的解剖 肺部。IL-17促进CXCR2配体的产生，包括CXCL5，它具有 中性粒细胞的趋化和激活功能，尤其是在急性炎症时 回应。初步数据表明，IL-17增强了这些基因的表达 通过组蛋白修饰的趋化因子。尽管IL-17可以促进炎症 通过稳定编码CXCR2配体的mRNAs，表观遗传调控 这项建议中描述的是新的，并可能对治疗产生重大的临床影响 以及慢性炎症性疾病的诊断。我们假设IL-17能增强 上皮细胞通过增加染色质产生CXCR2配体 通过抑制HDAC5和IL-17诱导的上皮CXCL5的可达性 肺部慢性中性粒细胞炎症所需。在Aim1，我们将 确定上皮性IL-17受体在调节CXCL5最佳表达中的作用 慢性炎症的中性粒细胞募集。我们将使用有条件的IL-17R KO 在已建立的小鼠模型中，小鼠模拟人类的中性粒细胞肺病。在……里面 我们将确定IL-17诱导的CXCR2配体的表达是否需要 组蛋白脱乙酰酶HDAC5，从初步研究中鉴定。在Aim3中，我们将 使用干扰化合物寻求在体内抑制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 为了最大限度地发挥靶向IL-17途径治疗慢性炎症的临床益处 明确IL-17驱动趋化因子表达的表观遗传学机制。这 应用寻求通过以下方式转变当前的研究和临床实践范式 一种新的IL-17促进表观遗传调控机制的鉴定 CF上皮中性粒细胞炎症。从这些目标中产生的结果可能 不仅对慢性粒细胞白血病，而且对其他中性粒细胞都有深刻的翻译意义 炎症状态。