Immune responses of the epithelium in chronic rhinosinusitis with polyps

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内科和外科治疗，其特征在于鼻窦粘膜的持续嗜酸性炎症，伴有经常被细菌和/或真菌定殖的增厚的分泌物。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，作为屏障和第一道防线抵御吸入的病原体和其他潜在的威胁。在过去的资助期间，我们研究了鼻窦上皮细胞（SNEC）如何通过产生先天性嗜酸性粒细胞介质和与适应性免疫系统的双向通信来促进CRSwNP。我们使用人体组织和小鼠模型的研究表明，SNEC由上皮损伤触发，产生促进嗜酸性粒细胞炎症的介质。我们假设这一通路是愈合和修复的正常方面，但受到与微生物感染相关的信号的抑制。为了验证这些假设，我们将首先在目标1中检查急性和慢性鼻窦炎性疾病患者的鼻窦粘膜，以确定干预后缓解期前嗜酸性粒细胞介质表达的模式。我们还将探讨在体外的相互作用的损伤相关分子，微生物的分子模式，和Th1细胞因子在确定SNEC亲嗜酸性粒细胞基因的表达。在目标2中，我们将利用鼻腔鼻窦嗜酸性粒细胞炎症小鼠模型与缺乏抗菌免疫相关基因的敲除小鼠相结合。作为这一目标的一部分，将产生第一个慢性鼻窦炎的转基因动物模型，具有进一步广泛的未来CRSwNP研究的巨大潜力。 最后，在目标3中，我们将剖析调节CRSwNP患者来源的SNEC中异常嗜酸性粒细胞前介质表达的亚细胞途径。这些研究将大大推进目前对CRSwNP的了解，并为这种令人衰弱和昂贵的医疗条件创造一个开发创新疗法的机会。

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. 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. During the past funding period, we investigated how sinonasal epithelial cells (SNEC) contribute to CRSwNP through production of innate pro-eosinophilic mediators and by bidirectional communication with the adaptive immune system. Our studies 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 is a normal aspect of healing and repair, but is suppressed by signals associated with microbial infection. To test these hypotheses, we will initially, in aim 1, examine sinus mucosa from patients with acute and chronic sinus inflammatory disease to define the pattern of pro-eosinophilic mediator expression during the resolution phase after intervention. We will also explore in vitro the interplay of damage-associated molecules, microbial molecular patterns, and Th1 cytokines in determining SNEC pro-eosinophilic gene expression. In aim 2, we will utilize mouse models of sinonasal eosinophilic inflammation in combination with knockout mice that lack antimicrobial immunity-associated genes. As part of this aim, the first transgenic animal model of chronic rhinosinusitis will be generated, with great potential to further a wide range of future CRSwNP research. Finally, in aim 3, we will dissect subcellular pathways that regulate abnormal pro-eosinophilic mediator expression in SNEC derived from CRSwNP patients. These studies will significantly advance current knowledge about CRSwNP and create an opportunity to develop innovative therapies for this debilitating and costly medical condition.