Dysfunction of Innate Immunity in Asthma

哮喘是一种疾病，表现为慢性炎症，并因环境侮辱而加剧，如 过敏原、感染剂和刺激物。固有的和适应性的宿主反应识别并根除 这些侮辱对恢复组织完整性和动态平衡的影响。在我们的提案中，我们将重点放在关键 天然免疫因子表面活性蛋白A(SP-A)是表面活性物质的一种脂质成分，棕榈酰油酰-油酰- 磷脂酰甘油(POPG)和Toll样受体相互作用蛋白(Tollip)。我们证明了这些 每个调节剂都执行关键的负面调节功能，这些功能相互协同，提供对II型的保护 炎症和病毒加重。SP-A调节与2型炎症相关的炎症和 病毒感染，但表现出遗传异质性，改变其功能。Tollip，一个30 kDa的适配器蛋白，是 也具有遗传异质性，被认为是Toll样受体(TLR)信号的负调节因子。一个 表面活性物质中含有磷脂，POPG通过以下途径在调节先天免疫中发挥关键作用 抑制多个TLR的激活。我们要检验的中心假设是SP-A功能障碍， Tollip和POPG的发生是遗传多态和退化事件的结果， 显著改变它们在哮喘和病毒感染环境中的功能，导致病情恶化 和顽固性炎症。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加重模型(鼻病毒、呼吸道 合胞病毒(RSV)，2型炎症(IL-13暴露，HDM动物模型)来自不同的分子 视角(SP-A、Tollip、POPG)，有效地创建了一种网络而不是线性方法来理解 2型炎症和哮喘加重时先天免疫功能障碍的机制(S)。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依赖的信号通路，但由于遗传异质性，其 哮喘患者的功能受损。特定的SP-A多肽可以挽救这种功能障碍，提供了一种新的 哮喘的治疗方法。项目2将确定基因决定的 2型炎症环境中Tollip表达和对病毒感染的呼吸道反应的变化。 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 阻断由轮状病毒和呼吸道合胞病毒引起的感染，这两种病毒已知会加剧哮喘。我们还包括两个 核心：管理核心和临床核心，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、人文主题和数据管理/统计方面。在……里面 在这个U19项目中，我们提出了先天性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与病原体的相互作用 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.