Dysfunction of Innate Immunity in Asthma

哮喘的先天免疫功能障碍

• 批准号: 9156365
• 负责人: Monica Kraft
• 金额: $ 142.82万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9156365
• 关键词: Adaptor Signaling Protein; Agonist; Allergens; Allergic Disease; Allergic inflammation; Animal Model; Asthma; Binding; Biology; Bronchoalveolar Lavage; Bronchoscopy; Cessation of life; Chest; Chronic; Clinical; Collaborations; Collectins; Communication; Coughing; Disease; Event; Exhibits; Functional disorder; Genetic Heterogeneity; Genetic Polymorphism; Genotype; Homeostasis; Hospitalization; Human; IRAK1 gene; Immune; Immune System Diseases; Immune response; Infection; Infectious Agent; Inflammation; Inflammatory; Interleukin-1; Interleukin-13; Invaded; Irritants; Lead; Lipids; Lung; Mediator of activation protein; Modeling; Molecular; Natural Immunity; Participant; Pathway interactions; Patients; Peptides; Phenotype; Phosphatidylglycerols; Phospholipids; Phosphotransferases; Physiological; Play; Predisposition; Preparation; Process; Public Health; Pulmonary Surfactant-Associated Protein A; RIPK1 gene; Receptor Signaling; Recombinants; Recruitment Activity; Research; Resolution; Resources; Respiratory Syncytial Virus Infections; Respiratory syncytial virus; Rhinovirus; Role; Sampling; Severities; Shipping; Ships; Signal Pathway; TOLLIP gene; Testing; Tissues; Toll-like receptors; Variant; Viral; Virus; Virus Diseases; Wheezing; clinically relevant; data management; genetic variant; human data; human subject; loss of function; lung injury; novel; novel therapeutic intervention; novel therapeutics; pathogen; programs; protein expression; receptor; response; surfactant

Asthma is disease manifested by chronic inflammation exacerbated by environmental insults such as allergens, infectious agents and irritants. The innate and adaptive host responses recognize and eradicate the effect of these insults to restore tissue integrity and homeostasis. In our proposal, we focus on the critical innate immune factors surfactant protein A (SP-A), a lipid constituent of surfactant, palmitoyl-oleoyl- phosphatidylglycerol (POPG) and Toll-like receptor interacting protein (Tollip). We show that these mediators each perform critical negative regulatory functions that synergize to offer protection from type 2 inflammation and viral exacerbations. SP-A modulates inflammation associated with type 2 inflammation and viral infections but exhibits genetic heterogeneity altering its function. Tollip, a 30 kDa adaptor protein that is also genetically heterogeneous, is recognized as a negative regulator of toll-like receptor (TLR) signaling. A phospholipid contained in surfactant, POPG is known to play a critical role in regulating innate immunity by inhibiting activation of multiple TLRs. Our central hypothesis to be tested is that dysfunction of SP-A, Tollip and POPG occurs as a consequence of genetic polymorphisms and degradative events which significantly alter their function in the setting of asthma and viral infection, leading to exacerbations and persistence of inflammation. With an underpinning of innate immune dysfunction, the projects utilize distinct but overlapping clinically relevant models of exacerbations in asthma (rhinovirus (RV), respiratory syncytial virus (RSV)), type 2 inflammation (IL-13 exposure, HDM animal models) from distinct molecular perspectives (SP-A, Tollip, POPG), effectively creating a network rather than linear approach to understanding the mechanism(s) of innate immune dysfunction in type 2 inflammation and asthma exacerbations. This program proposes three interrelated projects: Project 1 will determine how SP-A suppresses allergic inflammation through disruption of IL-13-dependent signaling pathways, but due to genetic heterogeneity, its function is impaired in asthma. Specific SP-A peptides can rescue this dysfunction, offering a novel therapeutic approach for asthma. Project 2 will determine the relationship between genetically determined variations in Tollip expression and airway responses to viral infections in the setting of type 2 inflammation. Project 3 will critically test the activity of POPG and SP-A as novel endogenous molecular mechanisms for disrupting infections due to RV and RSV, two viruses known to exacerbate asthma. We also include two cores: an Administrative Core and a Clinical Core, both which serve all projects equally and are responsible for the scientific, advisory, fiscal, human subject and data management/statistical aspects of the program. In this U19 program, we propose novel mechanisms of innate immune dysfunction and potential treatments that not only modulate the resolution of allergic inflammation, but regulate host-pathogen interactions in the setting of allergic inflammation.

哮喘是一种以慢性炎症为表现的疾病，这些炎症因环境损害而加剧，例如 过敏原、传染源和刺激物。先天的和适应性的宿主反应识别并消除 这些损伤对恢复组织完整性和体内平衡的影响。在我们的提案中，我们重点关注关键问题 先天性免疫因子表面活性剂蛋白 A (SP-A)，表面活性剂棕榈酰油酰基的脂质成分 磷脂酰甘油 (POPG) 和 Toll 样受体相互作用蛋白 (Tollip)。我们表明这些 每个介体都执行关键的负调节功能，协同作用以提供针对 2 型的保护 炎症和病毒恶化。 SP-A 调节与 2 型炎症相关的炎症 病毒感染，但表现出改变其功能的遗传异质性。 Tollip，一种 30 kDa 的接头蛋白， 也具有遗传异质性，被认为是 Toll 样受体 (TLR) 信号传导的负调节因子。一个 POPG 是表面活性剂中含有的磷脂，已知在调节先天免疫方面发挥着关键作用 抑制多个 TLR 的激活。我们要测试的中心假设是 SP-A 功能障碍， Tollip 和 POPG 的发生是遗传多态性和降解事件的结果， 显着改变其在哮喘和病毒感染中的功能，导致病情加重 以及炎症的持续存在。在先天免疫功能障碍的基础上，这些项目利用 不同但重叠的临床相关哮喘恶化模型（鼻病毒（RV）、呼吸系统疾病） 合胞病毒 (RSV))、来自不同分子的 2 型炎症（IL-13 暴露、HDM 动物模型） 视角（SP-A、Tollip、POPG），有效地创建网络而不是线性的理解方法 2 型炎症和哮喘恶化中先天免疫功能障碍的机制。这 该计划提出了三个相互关联的项目： 项目 1 将确定 SP-A 如何抑制过敏 通过破坏 IL-13 依赖性信号通路来抑制炎症，但由于遗传异质性，其 哮喘时功能受损。特定的 SP-A 肽可以挽救这种功能障碍，提供了一种新的方法 哮喘的治疗方法。项目2将确定基因决定之间的关系 2 型炎症环境中 Tollip 表达和气道对病毒感染反应的变化。 项目 3 将严格测试 POPG 和 SP-A 的活性，作为新的内源性分子机制 破坏 RV 和 RSV 引起的感染，这两种病毒已知会加剧哮喘。我们还包括两个 核心：行政核心和临床核心，两者平等地服务于所有项目并负责 用于该计划的科学、咨询、财政、人类主题和数据管理/统计方面。在 在这个 U19 项目中，我们提出了先天免疫功能障碍的新机制和潜在的治疗方法 不仅调节过敏性炎症的消退，还调节环境中宿主与病原体的相互作用 过敏性炎症。