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: 10259879
• 负责人: Justin H Turner
• 金额: $ 61.19万
• 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/10259879
• 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 慢性鼻窦炎（CRS）是一种常见的炎症性疾病，影响美国大部分地区。 造成受影响者的生活质量差，并使用数十亿美元的医疗保健 资源不幸的是，CRS更像是一种异质性综合征，而不是一个独特的诊断实体， 导致表型、症状和炎症特征的变异性。因此，CRS 疾病的病理生理学和相关机制仍然知之甚少。我们小组最近发现 一种老年CRS患者特有的独特炎症特征，其特征是严重升高 IL-1 β和其他促炎细胞因子。这一建议的核心假设是，老年人的CRS 患者与年龄依赖性、IL-1 β相关机制相关， 先天免疫和炎性小体的激活。我们将通过分析一个大型的 CRS患者的前瞻性入组队列。具体目标1将确定老化是否与 Toll样受体表达或功能改变，导致先天免疫系统的“启动”。目标2将 确定CRS患者的衰老是否导致炎性小体激活增加。我们随后将 分析常见微生物配体和内源性年龄相关炎症刺激物激活 炎性小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 鼻窦微生物组和/或单个病原体与衰老之间存在功能关联， 先天免疫功能和IL-1 β驱动的促炎信号。该提案旨在描述一个 以前未被识别的CRS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。本研究的结果将为进一步了解 CRS和揭示了先天免疫功能，窦微生物群， 不同类型的慢性粘膜炎症在鼻腔鼻窦。