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Innate Immune Regulation of the Epithelium in Chronic Rhinosinusitis with Nasal Polyps

慢性鼻窦炎伴鼻息肉上皮的先天免疫调节

基本信息

批准号：
10343709
负责人：
ANDREW P LANE
金额：
$ 53.31万
依托单位：
JOHNS HOPKINS UNIVERSITY
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：
2018-03-07 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10343709
关键词：
3-Dimensional Acute Adrenal Cortex Hormones Air Animal Model Apical Attention Automobile Driving Basal Cell CD34 gene Cell Communication Cell Culture Techniques Cell Differentiation process Cell Proliferation Cell surface Cells Characteristics Chronic Coculture Techniques Communication Cytokine Signaling Defect Disease Epithelial Epithelial Cells Failure Flow Cytometry Gene Expression Profile Genetic Transcription Growth Factor Health Homeostasis Human Immune Immunity Immunohistochemistry Individual Infection Inflammation Inflammatory Inhalation Injury Innate Immune Response Innovative Therapy Investigation Knowledge Lead Lesion Liquid substance Lung Lymphoid Cell Mediator of activation protein Medical Medical Care Costs Modeling Molecular Mucositis Mucous Membrane Mucous body substance Mus Nasal Polyps Natural Immunity Natural regeneration Nose Operative Surgical Procedures Organoids Pathogenesis Pathway interactions Patients Pattern Pharmaceutical Preparations Phenotype Physiological Play Polyps Population Process Production Property Proto-Oncogene Protein c-kit Regulatory T-Lymphocyte Reporting Research Rhinovirus infection Role STAT3 gene Sampling Secretory Cell Signaling Molecule Sinus Sinusitis Source TSLP gene Testing Therapeutic Thick Tissue Model Tissues United States Work antimicrobial chronic rhinosinusitis cost cytokine eosinophilic inflammation epithelial repair healing human tissue immunoregulation improved in vivo injury and repair innate immune function interleukin-22 microorganism mouse model novel novel therapeutic intervention pathogen polyposis receptor expression repaired stem cells

项目摘要

Chronic rhinosinusitis with polyps (CRSwNP) is a significant health problem in the United States. This disorder, which is often particularly recalcitrant to medical and surgical therapy, is characterized by persistent eosinophilic inflammation of the sinonasal mucosa, with thickened secretions that are frequently colonized with micro-organisms. The cellular and molecular mechanisms that underlie CRSwNP remain poorly understood. The epithelium of nose and sinuses participates actively in host immunity, serving as a barrier and first line of defense against inhaled pathogens and other potential threats. In previous studies, we investigated how sinonasal epithelial cells (SNEC) contribute to CRSwNP through production of innate pro-eosinophilic mediators and by bidirectional communication with other immune cells. Our research using human tissue and mouse models have suggested that SNEC are triggered by epithelial damage to produce mediators that promote eosinophilic inflammation. We hypothesize that this pathway, involving innate lymphoid cells (ILCs), is a normal aspect of healing and repair. Our latest findings suggest that the populations of ILCs and epithelial basal progenitor cells differ in CRSwNP. To test the hypotheses regarding basal cell and ILC interaction, we will initially, in aim 1, examine sinus mucosa from patients with chronic sinus inflammatory disease to define subtypes of basal progenitor cells and explore their innate immune function and pro-eosinophilic mediator expression. We will also employ novel cell culture models to understand the properties of basal cell populations. In aim 2, we will explore type 2 ILCs in CRSwNP and their interaction with basal cell populations, using cell culture models. Finally, in aim 3, we will investigate the innate immune activity of polyp basal cells in a modified cell culture model, and we will utilize genetically-modified mice and nasal inflammation models to explore the role of innate immune regulation of basal cells in healing and persistence of eosinophilic inflammation after injury. These studies will significantly advance current knowledge about CRSwNP and create an opportunity to develop innovative therapies for this debilitating and costly medical condition.

慢性鼻窦炎伴息肉（CRSwNP）在美国是一个重要的健康问题。这通常对内科和外科治疗特别不利的疾病的特征是持续性的，鼻窦鼻粘膜的嗜酸性炎症，伴有增厚的分泌物，经常定植有微生物CRSwNP的细胞和分子机制仍然知之甚少。鼻和鼻窦的上皮细胞积极参与宿主免疫，作为屏障和第一线，防御吸入的病原体和其他潜在威胁。在以前的研究中，我们调查了鼻窦上皮细胞（SNEC）通过产生先天性前嗜酸性粒细胞介体和与其他免疫细胞的双向通信。我们的研究使用人体组织，小鼠模型表明，SNEC由上皮损伤触发，产生促进细胞增殖的介质，嗜酸性炎症我们假设，这一途径，涉及先天性淋巴细胞（ILC），是一个正常的愈合和修复。我们最新的研究结果表明，ILC和上皮细胞的数量基底祖细胞在CRSwNP中不同。为了检验关于基底细胞和ILC相互作用的假设，我们在目标1中，我将首先检查慢性鼻窦炎性疾病患者的鼻窦粘膜，基底祖细胞亚型，并探讨其先天免疫功能和促嗜酸性粒细胞介质表情我们还将采用新的细胞培养模型来了解基底细胞的性质，人口。在目标2中，我们将探索CRSwNP中的2型ILC及其与基底细胞群的相互作用，使用细胞培养模型。最后，在aim3中，我们将研究息肉基底细胞的先天免疫活性在改良的细胞培养模型中，我们将利用基因修饰的小鼠和鼻腔炎症模型探讨基底细胞的天然免疫调节在嗜酸性粒细胞性白血病愈合和持续中的作用。损伤后的炎症。这些研究将大大推进目前关于CRSwNP的知识，为这种使人衰弱和昂贵的医疗状况创造一个开发创新疗法的机会。