Immune Responses of the Epithelium in Chronic Rhinosinusitis with Polyps

慢性鼻窦炎伴息肉上皮的免疫反应

• 批准号: 7925224
• 负责人: ANDREW P LANE
• 金额: $ 19.17万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-22 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7925224
• 关键词: Acute; Adopted; Agonist; Air; Animal Model; Bacteria; Biochemical; Biological Assay; Breathing; Cell Culture System; Cells; Characteristics; Chronic; Disease; Early Diagnosis; Epithelial Cells; Epithelium; Exposure to; Future; Gene Expression; Genes; Health; Homeostasis; Human; Immune; Immune response; Immunity; In Vitro; Inflammation; Inflammatory; Innovative Therapy; Interleukin-4; Knowledge; Lead; Ligands; Liquid substance; Mediator of activation protein; Medical; Mitogen-Activated Protein Kinases; Modeling; Molecular; Mucous Membrane; Mus; Nasal Polyps; Operative Surgical Procedures; Parasites; Particulate; Pathogenesis; Pathway interactions; Patients; Pattern; Pattern recognition receptor; Phenotype; Physiological; Play; Polyps; Process; Proteins; Research; Research Personnel; Role; Sentinel; Sinus; Specimen; Techniques; Testing; Tissue Sample; Toll-like receptors; Transgenic Animals; United States; Viral; Virus; acidic mammalian chitinase; antimicrobial; chronic rhinosinusitis; cytokine; fungus; human disease; immune function; in vivo; information gathering; microbial; model development; mouse model; novel therapeutic intervention; overexpression; pathogen; programs; promoter; respiratory; response; rhinosinusitis

DESCRIPTION (provided by applicant): 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 bacteria and/or fungi. The cellular and molecular mechanisms that underlie CRSwNP remain poorly understood. Epithelial cells of the sinonasal tract play important roles in host immune defense of the upper airway. They express pattern recognition receptors and produce anti-microbial effectors in response to inhaled pathogens. Innate immune pathways of sinonasal epithelial cells (SNECs) also promote Th1-like inflammation to target bacteria, viruses, and fungi. However, there are no identified innate immune programs of SNECs that generate Th2-like inflammation. Our preliminary studies strongly suggest that such an innate immune pathway exists in SNECs and, importantly, that activation of this pathway down-regulates innate anti-microbial activity in CRSwNP. We hypothesize that SNECs in CRSwNP are influenced by local Th2 cytokines and particular lumenal pathogen-associated molecules to adopt an "anti-parasite" innate immune program, characterized by expression of pro-eosinophilic mediators and suppression of anti-microbial function, thus promoting the cardinal features of CRSwNP. To further explore this hypothesis, we will initially, in aim 1, examine tissue samples from control subjects and well-characterized patients with chronic rhinosinusitis with and without nasal polyps, to fully characterize the anti-parasite pattern of gene expression in vivo. We will explore in vitro whether this phenotype results in reduced anti-microbial responses by SNECs to toll-like receptor agonists. In aim 2, we will use an air-liquid interface cell culture system to drive SNECs to the anti-parasite phenotype through exposure to Th2 cytokines and putative parasite-associated molecules. We will utilize this model to characterize the effect on innate anti-microbial function and identify underlying molecular mechanisms. Finally, in aim 3 we will create a genetically-modified mouse model of inducible Th2 sinonasal inflammation. We will examine whether our mouse model recapitulates important features of the human disease, and study whether chronic sinonasal Th2 inflammation in vivo leads to impaired innate anti-microbial function. Development of this model will provide the first transgenic animal model of chronic rhinosinusitis, which will have great potential to further a wide range of future CRSwNP research. These combined studies described in the proposal will significantly advance current knowledge about CRSwNP and potentially lead to innovative therapies for this debilitating and costly medical condition.

描述（由申请人提供）：慢性鼻窦炎伴息肉 (CRSwNP) 在美国是一个严重的健康问题。这种疾病通常特别难以接受药物和手术治疗，其特征是鼻窦粘膜持续性嗜酸性粒细胞炎症，分泌物增厚，经常有细菌和/或真菌定殖。 CRSwNP 背后的细胞和分子机制仍知之甚少。鼻窦上皮细胞在上呼吸道宿主免疫防御中发挥重要作用。它们表达模式识别受体并产生抗微生物效应物以响应吸入的病原体。鼻窦上皮细胞 (SNEC) 的先天免疫通路也会促进针对细菌、病毒和真菌的 Th1 样炎症。然而，尚未发现 SNEC 产生 Th2 样炎症的先天免疫程序。我们的初步研究强烈表明，SNEC 中存在这样的先天免疫通路，重要的是，该通路的激活会下调 CRSwNP 中的先天抗微生物活性。我们假设 CRSwNP 中的 SNEC 受到局部 Th2 细胞因子和特定腔内病原体相关分子的影响，采取“抗寄生虫”先天免疫程序，其特征是表达促嗜酸性粒细胞介质并抑制抗微生物功能，从而促进CRSwNP 的主要特征。为了进一步探讨这一假设，我们首先在目标 1 中检查来自对照受试者和患有或不患有鼻息肉的慢性鼻窦炎患者的组织样本，以充分表征体内基因表达的抗寄生虫模式。我们将在体外探索这种表型是否会导致 SNEC 对 Toll 样受体激动剂的抗微生物反应降低。在目标 2 中，我们将使用气液界面细胞培养系统，通过暴露于 Th2 细胞因子和假定的寄生虫相关分子，将 SNEC 驱动至抗寄生虫表型。我们将利用该模型来表征对先天抗微生物功能的影响并确定潜在的分子机制。最后，在目标 3 中，我们将创建诱导型 Th2 鼻腔炎症的转基因小鼠模型。我们将检查我们的小鼠模型是否重现了人类疾病的重要特征，并研究体内慢性鼻腔 Th2 炎症是否会导致先天抗微生物功能受损。该模型的开发将提供第一个慢性鼻窦炎转基因动物模型，这对于进一步开展广泛的 CRSwNP 研究具有巨大潜力。提案中描述的这些综合研究将显着推进当前关于 CRSwNP 的知识，并有可能为这种令人衰弱且昂贵的医疗状况带来创新疗法。