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.

项目概要 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。 人口，导致受影响者的生活质量较差，并需要花费数十亿美元的医疗保健 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、症状和测试的炎症特征的变异。 我们小组最近发现的疾病的病理生理学和相关机制仍然知之甚少。 老年 CRS 患者特有的独特炎症特征，其特征是显着升高 IL-1 和其他促炎细胞因子的作用 该提案的中心假设是老年人中存在 CRS。 患者与年龄依赖性、IL-1相关机制相关，该机制源于功能失调 我们将通过分析大量数据来检验这一假设。 前瞻性纳入的 CRS 患者队列将确定衰老是否与衰老相关。 改变 Toll 样受体的表达或功能，从而“启动”先天免疫系统。 随后我们将确定 CRS 患者的衰老是否会导致炎症小体激活增加。 分析常见微生物配体和内源性年龄相关炎症刺激的激活能力 最后，在具体目标 3 中，我们将确定是否存在与炎症小体相关的细胞因子的产生和释放。 鼻腔微生物组和/或个体病原体与衰老之间存在功能关联， 该提案旨在描述先天免疫功能和 IL-1 驱动的促炎症特征。 以前未被识别的 CRS 炎症亚型影响老年人，这是一个易受感染的人群 这项研究的有限的医疗和手术选择将提供对机制的进一步了解。 CRS 并揭示了先天免疫功能、鼻窦微生物群和 鼻窦内不同类型的慢性粘膜炎症。