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DNA induction of neutrophilic asthma

DNA诱导中性粒细胞性哮喘

基本信息

批准号：
10343318
负责人：
Rafeul Alam
金额：
$ 47.05万
依托单位：
NATIONAL JEWISH HEALTH
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-17 至 2026-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10343318
关键词：
Abbreviations Adaptor Signaling Protein Adjuvant Agreement Allergens Allergic Alternaria Aluminum Hydroxide Alveolar Macrophages Anti-Inflammatory Agents Asthma Biopsy Specimen Blood donor Bronchoalveolar Lavage Cadaver Cells Confocal Microscopy DNA Data Deoxyribonucleases Development Epithelial Cells Excision Extracellular Fluid Family Fc Receptor Flow Cytometry Generations Human Immunofluorescence Immunologic Infection Inflammasome Inflammation Inflammatory Interferon Type I Interferon Type II Interferons Interleukin-1 Interleukin-10 Interleukin-2 Knockout Mice Lipofectamine Lung Mediating Modeling Molecular Mus Nose Nucleosomes Orthologous Gene Outcome Study Pathologic Processes Pathology Pathway interactions Pattern Peripheral Blood Mononuclear Cell Phenotype Proteins Refractory Rhinovirus Role STING1 gene Serum Signal Transduction Stains Stimulator of Interferon Genes Subgroup T memory cell TNF gene TNFSF4 gene Therapeutic Virus airway hyperresponsiveness asthma exacerbation asthma model asthmatic patient base bronchial epithelium chemokine cytokine disorder control effective therapy eosinophilic asthma eosinophilic inflammation extracellular human DNA inhibitor/antagonist macrophage monocyte mouse model neutrophil new therapeutic target novel novel therapeutics peripheral blood preclinical study programs sensor targeted treatment therapeutic evaluation transcriptomics

项目摘要

PROJECT SUMMARY Neutrophilic asthma is a subtype of severe asthma, which has no safe and effective therapy. There is an unmet need to delineate the mechanism of neutrophilic asthma and develop targeted and effective therapies. Host cell-derived DNA is present in the extracellular fluid and serum. DNA represents a danger signal (danger- associate molecular pattern-DAMP) for host cells. Recent studies suggest an important role for extracellular DNA in mediating virus-induced asthma exacerbation. We present robust preliminary data demonstrating increased levels of extracellular DNA, the DNA sensor IFI16 (Interferon-gamma induced protein-16) and the DNA-IFI16 pathway-driven cytokines/chemokines in the airways from neutrophilic asthma. We developed a mouse model of asthma where DNA induces neutrophilic inflammation in the context of an IL10-constrained inflamed airway milieu. This phenotype requires the participation of the IFI16 signaling adapter STING. Based upon these novel preliminary results we hypothesize that extracellular DNA induces neutrophilic asthma through the IFI16-STING pathway in the presence of select IL10-suppressive TNFSFs. Neutrophil extracellular traps generate DNA, which establishes a self-perpetuated mechanism of neutrophilic asthma. Under Aim 1 we will examine the relevance of extracellular DNA for human neutrophilic asthma. We will study the generation of airway extracellular DNA, activation of IFI16 and IL10-suppressive TNFSFs—TNF and OX40L and their pathophysiological consequences in the airways. We will study bronchoalveolar lavage (BAL), bronchial epithelial cells and biopsy specimens from 3 study groups: 1) Neutrophilic (with and without eosinophilic) asthma; 2) Non-neutrophilic (with and without eosinophilic) asthma; and 3) Disease controls. We will delineate the function and importance of IFI16 for proneutrophilic biomolecules in a reductionist model in DNA-treated airway macrophages and blood monocytes. Under Aim 2 we will study the mechanism of extracellular DNA- induced neutrophilic asthma in mice. We will elucidate the role of IL10 and TNFSFs (TNF and OX40L) in switching the DNA-induced defensive program to a neutrophilic inflammation program in mouse airways. We will establish the role of IFI204 (the mouse IFI16 ortholog) and STING in neutrophilic inflammation. We will study the effect of removal of extracellular DNA on persistence of neutrophilic asthma in mice. This project is important because it uncovers a novel DNA-IFI16-STING mechanism of neutrophilic asthma and assesses the therapeutic benefits of DNA and STING inhibitors, and DNA scavengers in a preclinical study.

项目摘要嗜中性粒细胞哮喘是严重哮喘的一种亚型，目前尚无安全有效的治疗方法。有一个描述嗜酸性哮喘的机制并开发靶向和有效的治疗方法的需求尚未得到满足。宿主细胞衍生的DNA存在于细胞外液和血清中。DNA代表危险信号（危险- 相关分子模式-DAMP）。最近的研究表明，细胞外 DNA介导病毒诱导的哮喘急性发作我们提出了强有力的初步数据证明，细胞外DNA、DNA传感器IFI 16（干扰素-γ诱导蛋白-16）和嗜肺性哮喘气道中DNA-IFI 16通路驱动的细胞因子/趋化因子我们开发了一个哮喘小鼠模型，其中DNA在IL 10-限制性的环境中诱导嗜酸性炎症。气道环境发炎这种表型需要IFI 16信号转导衔接子STING的参与。基于根据这些新的初步结果，我们假设细胞外DNA诱导嗜酸性哮喘，通过IFI 16-STING途径在选择的IL 10抑制性TNFSF的存在下。中性粒细胞胞外陷阱产生DNA，这建立了嗜酸性哮喘的自我延续机制。根据目标1，将研究细胞外DNA与人类嗜酸性哮喘的相关性。我们将研究气道细胞外DNA、IFI 16和IL 10抑制性TNFSFs-TNF和OX 40 L的活化及其气道中的病理生理学后果。我们将研究支气管肺泡灌洗（BAL），支气管来自3个研究组的上皮细胞和活检标本：1）嗜中性粒细胞（伴和不伴嗜酸性粒细胞）哮喘; 2）非嗜酸性粒细胞性（有和没有嗜酸性粒细胞性）哮喘;和3）疾病对照。我们将描绘 IFI 16在DNA处理还原模型中对亲嗜中性生物分子的功能和重要性气道巨噬细胞和血液单核细胞。根据目标2，我们将研究细胞外DNA的机制- 诱发小鼠嗜肺性哮喘。我们将阐明IL 10和TNFSF（TNF和OX 40 L）在在小鼠气道中将DNA诱导的防御程序转换为嗜酸性炎症程序。我们将建立IFI 204（小鼠IFI 16直系同源物）和STING在嗜中性炎症中的作用。我们将研究去除细胞外DNA对小鼠嗜酸性哮喘持续存在的影响。这个项目是重要的是，它揭示了一种新的DNA-IFI 16-STING嗜酸性哮喘机制，并评估了 DNA和STING抑制剂以及DNA清除剂在临床前研究中的治疗益处。