Der p 2-driven TLR4 signaling in allergic asthma

过敏性哮喘中 Der p 2 驱动的 TLR4 信号传导

• 批准号: 8201842
• 负责人: Jaclyn W McAlees
• 金额: $ 5.32万
• 依托单位: CINCINNATI CHILDRENS HOSP MED CTR
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-09-01 至 2013-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8201842
• 关键词: Adjuvant; Allergens; Antigen-Presenting Cells; Automobile Driving; Binding; Biological; Cell Line; Cell surface; Cells; Chronic; Chronic lung disease; Complex; Data; Dendritic Cells; Dermatophagoides pteronyssinus antigen p 2; Development; Endosomes; Epithelial Cells; Experimental Models; Extrinsic asthma; Genetic; Goals; House Dust Mite Allergens; IRF3 gene; Immune response; Immune system; Inflammation; Inflammatory; Interferons; Laboratories; Lung diseases; Measures; Mediating; Mediator of activation protein; Molecular; Molecular Mimicry; Mus; Myeloid Cells; Pathway interactions; Phase; Prevalence; Preventive; Production; Proteins; Recruitment Activity; Respiratory physiology; Signal Pathway; Signal Transduction; Signal Transduction Pathway; System; TLR4 gene; Therapeutic; Transgenic Mice; Work; activating transcription factor; allergic airway inflammation; base; chemokine; cytokine; in vivo; mouse model; reconstitution; research study; response

DESCRIPTION (provided by applicant): Allergic asthma is thought to result from Th2-polarized immune responses to otherwise apparently innocuous environmental proteins. Why specific proteins drive such maladaptive immune responses in susceptible hosts has been unclear. Our lab and others have suggested that direct, (dys)functional interactions between such proteins and the innate immune system are central to the molecular basis of allergenicity. In the case of Der p 2, a major house dust mite allergen, our data indicate that it tends to be a target of adaptive immune responses because it has intrinsic adjuvant activity due to its molecular mimicry of MD-2, the LPS-binding subunit of the TLR4 complex. Der p 2 can reconstitute and augment TLR4 signaling in the absence and presence of MD-2, respectively. In addition, Der p 2 drives TLR4-dependent, MD- 2-independent Th2-polarized inflammation in the airways of mice. Recent data suggest that the relevant locus of TLR4 signaling important for driving Th2 inflammation in the airway involves TLR4 signaling by airway epithelial cells (AECs), which regulate the development of aeroallergic responses via the production of chemokines and cytokines that recruit and regulate the function of lung dendritic cells. MD-2-dependent TLR4 signaling involves activation of both Mal/MyD88 and TRIF/TRAM pathways of signal transduction. The molecular mechanisms underlying Der p 2-dependent TLR4 signaling remain to be defined. Based on preliminary data, we hypothesize that: (a) like MD-2, Der p 2 drives TLR4 signaling via both pathways; but (b) the allergenicity of Der p 2 is depends primarily on TRIF/TRAM signaling. The proposed experiments will define the signaling pathways activated by Der p 2-dependent TLR4 stimulation in genetically tractable cell lines; determine the Th2-polarizing cellular responses (and underlying signaling pathways) driven by Der p 2-driven TLR4 signaling in primary AECs; and define the TLR4-driven signaling pathways essential to the in vivo allergenicity of Der p 2 using genetic mouse models. The long-term goal of this proposal is to define the signaling pathways activated by Der p 2 and their biological consequences for aeroallergy, in order to devise new preventive and/or therapeutic strategies for allergic asthma. PUBLIC HEALTH RELEVANCE: Allergic asthma is often a debilitating chronic lung disease that has undergone a dramatic increase in prevalence in the developed world. The goal of this project is to understand how allergens induce the development of allergic asthma so that new preventive and/or therapeutic measures can be developed.

描述（由申请人提供）：过敏性哮喘被认为是由Th 2极化的免疫反应引起的，否则显然无害的环境蛋白。为什么特定的蛋白质在易感宿主中驱动这种适应不良的免疫反应还不清楚。我们的实验室和其他人已经提出，这些蛋白质和先天免疫系统之间的直接（dys）功能性相互作用是变应原性分子基础的核心。在Der p 2（一种主要的屋尘螨过敏原）的情况下，我们的数据表明，它往往是适应性免疫应答的靶点，因为它具有内在的佐剂活性，这是由于它对MD-2（TLR 4复合物的LPS结合亚基）的分子模拟。Der p 2可以分别在MD-2不存在和存在的情况下重建和增强TLR 4信号传导。此外，Der p 2驱动小鼠气道中的TLR 4依赖性、MD- 2非依赖性Th 2极化炎症。最近的数据表明，驱动气道中的Th 2炎症的重要的TLR 4信号传导的相关位点涉及气道上皮细胞（AEC）的TLR 4信号传导，其通过产生趋化因子和细胞因子来调节气道变态反应的发展，所述趋化因子和细胞因子募集和调节肺树突状细胞的功能。 MD-2依赖性TLR 4信号传导涉及信号转导的Mal/MyD 88和TRIF/TRAM途径的激活。Der p 2依赖性TLR 4信号转导的分子机制仍有待确定。基于初步数据，我们假设：（a）与MD-2一样，Der p 2通过两种途径驱动TLR 4信号传导;但（B）Der p 2的变应原性主要取决于TRIF/TRAM信号传导。所提出的实验将定义在遗传上易处理的细胞系中由Der p 2依赖性TLR 4刺激激活的信号传导途径;确定在原代AEC中由Der p 2驱动的TLR 4信号传导驱动的Th 2极化细胞应答（和潜在的信号传导途径）;并使用遗传小鼠模型定义对Der p 2的体内变应原性至关重要的TLR 4驱动的信号传导途径。该提案的长期目标是确定由Der p 2激活的信号通路及其对空气过敏的生物学后果，以设计新的预防和/或治疗过敏性哮喘的策略。 公共卫生相关性：过敏性哮喘通常是一种使人衰弱的慢性肺部疾病，在发达国家的患病率急剧增加。该项目的目标是了解过敏原如何诱导过敏性哮喘的发展，以便开发新的预防和/或治疗措施。