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

慢性鼻-鼻窦炎合并息肉(CRSwNP)在美国是一个严重的健康问题。这 精神障碍通常对内科和外科治疗特别顽固，其特点是持续性 鼻腔粘膜嗜酸性炎症，分泌物增厚，常以 微生物。CRSwNP背后的细胞和分子机制仍然知之甚少。 鼻、鼻窦上皮积极参与宿主免疫，是机体免疫的屏障和第一线。 防御吸入病原体和其他潜在威胁。在之前的研究中，我们调查了 鼻窦上皮细胞(SNEC)通过产生先天嗜酸性粒细胞参与CRSwNP的形成 并通过与其他免疫细胞的双向通信来实现。我们的研究使用了人体组织和 小鼠模型表明SNEC是由上皮损伤触发的，以产生促进 嗜酸性炎症。我们假设，这条涉及先天淋巴样细胞(ILCs)的途径是一种 愈合和修复的正常方面。我们的最新发现表明，ILC和上皮细胞的数量 CRSwNP的基底层祖细胞不同。为了检验关于基底细胞和ILC相互作用的假设，我们 首先，在目标1中，检查慢性鼻窦炎性疾病患者的鼻窦粘膜以确定 基底祖细胞亚型及其天然免疫功能和嗜酸性粒细胞介体的探讨 表情。我们还将使用新的细胞培养模型来了解基底细胞的特性 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，在目标3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，我们将利用转基因小鼠和鼻炎模型 探讨基底细胞天然免疫调节在嗜酸性粒细胞修复和持续中的作用 受伤后的炎症。这些研究将大大促进对CRSwNP和CRSwNP的现有知识 创造一个机会，为这种令人虚弱和昂贵的疾病开发创新的疗法。

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.