Dysfunction of Innate Immunity in Asthma

哮喘是一种由慢性炎症引起的疾病， 过敏原、传染源和刺激物。宿主的先天性和适应性反应识别并消灭了 这些损伤恢复组织完整性和体内平衡的作用。在我们的建议中，我们专注于关键的 先天免疫因子表面活性剂蛋白A（SP-A），表面活性剂的脂质成分，棕榈酰-油酰- 磷脂酰甘油（POPG）和Toll样受体相互作用蛋白（Tollip）。我们发现这些 每个介质都执行关键的负调节功能，协同作用以提供对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是一种30 kDa的衔接蛋白， 也是遗传异质性的，被认为是Toll样受体（TLR）信号传导的负调节剂。一 作为表面活性剂中所含的磷脂，已知POPG在调节先天免疫中起关键作用， 抑制多种TLR的活化。我们要检验的中心假设是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， 在哮喘和病毒感染的情况下显著改变其功能，导致病情加重 和炎症的持续存在。以先天免疫功能障碍为基础，该项目利用 不同但重叠的哮喘急性发作的临床相关模型（鼻病毒（RV）、呼吸道病毒（RV）、呼吸道病毒（RV））， 合胞病毒（RSV））、2型炎症（IL-13暴露，HDM动物模型）， 观点（SP-A，Tollip，POPG），有效地创建了一个网络，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 炎症通过破坏IL-13依赖性信号通路，但由于遗传异质性， 功能在哮喘中受损。特异性SP-A肽可以挽救这种功能障碍，提供了一种新的治疗方法。 哮喘的治疗方法。项目2将确定基因决定的 Tollip表达的变化和2型炎症背景下对病毒感染的气道反应。 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， 破坏由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：一个行政核心和一个临床核心，两者都平等地为所有项目服务，并负责 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，而且调节环境中宿主-病原体相互作用， 过敏性炎症

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.