Age-associated Innate Immune Dysfunction in Chronic Rhinosinusitis

项目摘要 慢性鼻窦炎(CRS)是一种常见的炎症性疾病，影响美国很大一部分地区。 人口，导致受影响者的生活质量较差，并使用数十亿美元的医疗保健 资源。不幸的是，CRS更像是一种异质综合征，而不是一个独特的诊断实体， 导致表型、症状和炎症性征象的多样性。因此，CRS 病理生理学和相关的疾病机制仍然知之甚少。我们的团队最近确定了 一种独特的炎症征象，专用于老年CRS患者，特点是显著升高 IL-1、和其他促炎细胞因子的表达。这一建议的中心假设是老年人的CRS 患者与年龄相关的IL-1相关机制源于功能障碍 先天免疫和炎症小体的激活。我们将通过分析一个大型的 前瞻性登记的CRS患者队列。具体目标1将确定衰老是否与 改变Toll样受体的表达或功能，从而引发先天免疫系统的“启动”。目标2将 确定CRS患者的衰老是否导致炎症体激活增加。我们随后将 分析常见微生物配体和内源性AGE相关炎症刺激的激活能力 炎症体相关细胞因子的产生和释放。最后，在具体目标3中，我们将确定 鼻窦微生物群和/或个体病原体与衰老之间存在功能关联， 先天免疫功能，以及IL-1驱动的促炎信号。这项提案试图将一种 以前未发现的CRS炎症性亚型，影响老年人，易感人群 医疗和手术选择有限。这项研究的发现将为进一步深入了解 CRS并揭示了先天免疫功能、鼻窦微生物区系和 鼻腔内不同类型的慢性粘膜炎症。

Project Summary Chronic rhinosinusitis (CRS) is a common inflammatory disease that affects a large portion of the U.S. population, resulting in poor quality of life for those affected and utilizing billions of dollars of health care resources. Unfortunately, CRS presents more like a heterogeneous syndrome than a distinct diagnostic entity, resulting in variability in both phenotype, symptoms, and inflammatory signatures. Consequently, CRS pathophysiology and associated mechanisms of disease remain poorly understood. Our group recently identified a unique inflammatory signature specific to elderly CRS patients, which is characterized by profound elevation of IL-1 and other pro-inflammatory cytokines. The central hypothesis of this proposal is that CRS in aged patients is associated with an age-dependent, IL-1-associated mechanism that derives from dysfunctional innate immunity and activation of the inflammasome. We will test this hypothesis by analyzing a large prospectively enrolled cohort of CRS patients. Specific Aim 1 will determine whether aging is associated with altered Toll-like receptor expression or function, with resultant ‘priming’ of the innate immune system. Aim 2 will determine whether aging in CRS patients results in increased inflammasome activation. We will subsequently analyze the ability of common microbial ligands and endogenous age-related inflammatory stimuli to activate inflammasome-associated cytokine production and release. Finally, in Specific Aim 3 we will determine whether there are functional associations between the sinonasal microbiome and/or individual pathogens with aging, innate immune function, and the IL-1-driven pro-inflammatory signature. This proposal seeks to characterize a previously unrecognized inflammatory subtype of CRS that affects aged individuals, a vulnerable population with limited medical and surgical options. Findings from this study will provide further insight into the mechanism of CRS and reveal previously unidentified associations between innate immune function, the sinus microbiota, and different types of chronic mucosal inflammation in the sinonasal cavity.