Age-associated Innate Immune Dysfunction in Chronic Rhinosinusitis

慢性鼻窦炎与年龄相关的先天免疫功能障碍

• 批准号: 10456200
• 负责人: Justin H Turner
• 金额: $ 61.67万
• 依托单位: VANDERBILT UNIVERSITY MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-09-10 至 2025-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10456200
• 关键词: Adrenal Cortex Hormones; Affect; Age; Aging; Antibody Therapy; Asthma; Cells; Chronic; Clinical Research; Cohort Studies; Data; Data Analyses; Diagnostic; Disease; Elderly; Enrollment; Epithelial; Functional disorder; Genetic Transcription; Goals; Grant; Healthcare; Immune; Immune System Diseases; Immunophenotyping; In Vitro; Individual; Inflammasome; Inflammation; Inflammatory; Innate Immune System; Interleukin-1; Intervention; Lead; Ligands; Medical; Molecular; Mucositis; Mucous Membrane; Natural Immunity; Operative Surgical Procedures; Patients; Pattern; Phenotype; Population; Production; Prospective cohort; Quality of life; Receptor Signaling; Research Personnel; Resources; Risk; Role; Sampling; Sinus; Stimulus; Symptoms; Syndrome; System; Techniques; Testing; Tissue Procurements; Tissues; Toll-like receptors; Topical Corticosteroids; United States National Institutes of Health; Vulnerable Populations; age group; age related; aged; alternative treatment; base; chronic rhinosinusitis; cohort; comorbidity; cytokine; design; environmental allergy; epidemiology study; human tissue; humanized monoclonal antibodies; innate immune function; insight; interest; microbial; microbiome; microbiota; microorganism antigen; multidimensional data; multidisciplinary; multiple omics; nasal microbiome; neutrophil; novel; older patient; pathogen; pathogenic bacteria; pathogenic microbe; physical conditioning; prospective; receptor expression; receptor function; response; side effect; translational study; working group

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.

项目摘要 慢性鼻塞炎（CRS）是一种常见的炎症性疾病，影响美国大部分地区 人口，导致受影响和使用数十亿美元医疗保健的人的生活质量差 资源。不幸的是，CRS更像异质综合症，而不是独特的诊断实体， 导致表型，符号和炎症性特征的变异性。因此，CRS 病理生理学和疾病相关机制仍然很少了解。我们的小组最近确定 较老的CRS患者特有的独特炎症特征，其特征是高升高 IL-1和其他促炎细胞因子的摄入。该提议的中心假设是 患者与年龄相关的IL-1相关机制有关，该机制来自功能失调 先天免疫和炎症体的激活。我们将通过分析大型 前瞻性招募的CRS患者队列。特定目标1将确定衰老是否与 改变了Toll样受体表达或功能，导致了先天免疫系统的“启动”。 AIM 2意志 确定CRS患者的衰老是否会导致炎症体激活增加。我们将随后 分析常见微生物配体和内源性年龄相关炎症刺激的能力激活 与炎性体相关的细胞因子产生和释放。最后，在特定目标3中，我们将确定是否 鼻窦微生物组和/或各个病原体之间存在功能关联， 先天免疫功能和IL-1驱动的促炎性签名。该建议旨在表征 以前无法识别的CRS的炎症亚型影响老年人，一个脆弱的人群 有限的医疗和手术选择。这项研究的发现将进一步了解 CRS并揭示了先前未鉴定的先天免疫功能，鼻窦微生物群和 鼻窦腔中不同类型的慢性粘膜感染。