Immunobiology of Acute Environmental Asthma

急性环境哮喘的免疫生物学

• 批准号: 7901225
• 负责人: David B. Peden
• 金额: $ 85.2万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-12 至 2012-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7901225
• 关键词: Immunobiology; Acute; Environmental; Asthma

DESCRIPTION (provided by applicant): The focus of this U19 project, "Immunobiology of Acute Environmental Asthma", is to conduct mechanistic studies of the role of innate immune processes in mediation of acute environmental asthma. Epidemiological studies have clearly shown that asthma exacerbation linked to air pollutants is a major cause of asthma exacerbation. Endotoxin is a commonly encountered environmental pollutant found in ambient particulate matter and in occupational and domestic settings as well. Endotoxin can induce neutrophilic inflammation at high levels, and at low levels enhance response of asthmatics to airway allergen challenge. We have shown that endotoxin causes changes in airway monocytes and macrophages (increased CD14, CD80, Fc?RI and HLA-DR) which are associated with enhanced response to either innate or acquired immune stimuli. Our team has recently identified novel regulatory molecules of inflammation in the CATERPILLER family, specifically cryopyrin (which upregulates neutrophilic inflammation and monocytic function) and monarch-1, (which downregulates response to innate activation). Cryopyrin is of particular interest as it acts through formation of a Caspase-1 based inflammasome to cleave pro-IL-l? to active IL-1? (with downstream production of IL-6 and other mediators) and IL-18. Furthermore, cryopyrin is activated after ligation of either pathogen associated molecular pattern receptors (including CD14 facilitated binding of endotoxin by TLR4) or the P2X7 receptor by ATP (which is increasingly recognized as an endogenous danger signal released by host cells following non-specific cell injury). These dual activation pathways likely account for the similar actions of a wide variety of inhaled environmental contaminants, and represent novel targets for treatment of acute asthma. We will conduct mechanistic studies of the role of the CATERPILLER family members cryopyrin and monarch-1 (Project 1-J. Ting PI), and the role of NALP-1 and the purinergic receptor P2X7 (Project 2-B. Koller, PI) in rodent models of environmental asthma, in conjunction with a translational project (Project 3-D. Peden, PI) designed to determine the effect of interaction of endotoxin- and allergen-induced inflammation on the airway biology of allergic asthmatics. Human studies will be focused on the biology of airway monocytic cells and the expression of innate immune and the CATERPILLAR family of immune regulators and P2X7 receptors in the airway. In addition to assessment of the role of innate immune processes in regulating airway inflammation, we will examine the relationship of this inflammation on airway physiology, specifically mucociliary clearance. Decreased mucociliary clearance is an understudied process which mediates asthma exacerbation and is a feature of increased asthma severity. PROJECT 1: Novel and innate immune genes in asthma (TING, J) PROJECT 1 DESCRIPTION (provided by applicant): We recently discovered the CATERPILLER family which share structural similarities with the NB-LRR (nucleotide-binding, leucine-rich repeat) super-family of disease resistance (R) proteins that constitutes the plant immune system. In the animal kingdom, this family is also known as NOD or NLR. The clinical importance of this family is underscored by the genetic linkage of family members to a number of immunologic disorders. Among the human gene family members, several of these appear to mediate negative regulatory function in controlling an overzealous inflammatory response. Most notable is the Monarch-1 protein which blocks the function of NF-?B inducing kinase (NIK). Inhibition of NIK reduces the expression of an array of chemokines with relevance in asthma. Gene profiling of induced sputum from mildly asthmatic individuals suggests that the Monarch-1 gene is reduced in these individuals relative to controls, supporting the inhibitory role of this gene during inflammation. Another group of family members regulates IL-1 production. Most notable among these is cryopyrin which mediates formation of the inflammasome complex upon stimulation with a number of inducers. The inflammasome complex is required for procaspase 1 processing to mature caspase 1. In turn, caspase-1 is required for the processing of pro-IL-1 and pro-IL-18 to their mature forms. IL-1 and IL-18 are respectively important in inflammation and TH2 skewing. Cryopyrin is also important in mediating macrophage necrosis which exacerbates inflammation. Thus there are compelling reasons to believe that Monarch-1 and cryopyrin have crucial roles in asthma, however there is no in vivo data to indicate that this is the case. Furthermore we have shown that both of these proteins are ATP-binding proteins, and they exhibit ATPase activity, thus providing ways to modulate their function, which might be important leads to drug discovery. The goals of this proposal are: (1) To study the relevance of Monarch-1 in three animal models of asthma (OVA-induced, endotoxin, and house dust mite and delineate the biochemical effects of Monarch-1 in vivo and ex vivo. (2) To study the relevance of cryopyrin and a cryopyrin-adaptor (ASC) in asthma. (3) To study and identify factors which modulate the nucleotide-binding properties and ATPase function of Monarch-1 and cryopyrin.

描述（由申请人提供）：该U19项目的重点“急性环境哮喘的免疫生物学”是为了对先天免疫过程在急性环境哮喘的介导中的作用进行机械研究。流行病学研究清楚地表明，与空气污染物有关的哮喘加剧是哮喘加剧的主要原因。内毒素是在环境颗粒物以及职业和家庭环境中发现的一种常见的环境污染物。内毒素可以在高水平的高水平上诱导嗜中性炎性炎症，并且在低水平下会增强哮喘患者对气道过敏原挑战的反应。我们已经表明，内毒素会导致气道单核细胞和巨噬细胞的变化（CD14，CD80，FC？RI和HLA-DR），这与对先天或获得的免疫刺激的反应增强有关。我们的团队最近鉴定了毛毛虫家族中炎症的新型调节分子，特别是冷冻蛋白（上调中性炎性炎症和单核细胞功能）和君主-1（下调对先天激活的反应）。冷冻蛋白特别感兴趣，因为它通过形成基于caspase-1的炎症体来裂解pro-il-l？活跃IL-1？ （具有IL-6和其他介体的下游产生）和IL-18。此外，在与病原体相关的分子模式受体（包括TLR4通过TLR4促进结合CD14）或通过ATP的P2X7受体结合后，激活冷冻蛋白，越来越多地被认为是宿主细胞在非特异性细胞后释放的内源性危险危险信号）。这些双重激活途径可能解释了多种吸入环境污染物的相似作用，并代表了治疗急性哮喘的新靶标。 We will conduct mechanistic studies of the role of the CATERPILLER family members cryopyrin and monarch-1 (Project 1-J. Ting PI), and the role of NALP-1 and the purinergic receptor P2X7 (Project 2-B. Koller, PI) in rodent models of environmental asthma, in conjunction with a translational project (Project 3-D. Peden, PI) designed to determine the effect of interaction of endotoxin- and过敏原引起的过敏性哮喘患者的炎症。人类研究将集中于气道单核细胞的生物学以及先天免疫的表达以及气道中的免疫调节剂和P2X7受体的毛毛虫家族。除了评估先天免疫过程在调节气道炎症中的作用外，我们还将研究这种炎症对气道生理学的关系，特别是粘膜纤毛清除率。粘膜缩减清除率降低是一个研究的研究过程，可介导哮喘加重，并且是哮喘严重程度增加的特征。 项目1：哮喘中的新颖和先天免疫基因（Ting，J） 项目1描述（由申请人提供）：我们最近发现了Caterpiller家族，该家族与NB-LRR（核苷酸结合，含亮氨酸丰富的重复）具有疾病耐药性（R）蛋白质的超级家族相似性，该蛋白构成了植物免疫系统。在动物界，这个家庭也被称为点头或NLR。该家族的临床重要性强调了家庭成员与多种免疫疾病的遗传联系。在人类基因家族成员中，其中一些似乎介导了负调节功能，以控制过度狂热的炎症反应。最值得注意的是君主-1蛋白阻断NF-？b诱导激酶（NIK）的功能。 NIK的抑制作用降低了与哮喘相关的趋化因子阵列的表达。来自轻度哮喘患者诱导痰的基因分析表明，这些个体相对于对照组降低了君主-1基因，从而支持该基因在炎症过程中的抑制作用。另一组家庭成员调节IL-1的生产。其中最值得注意的是冷冻蛋白，它在用多种诱导剂刺激后介导炎性体复合物的形成。在成熟的caspase 1处理过程中，炎症体复合物是必需的。反过来，将pro-il-1和pro-il-18加工成成熟形式所必需的caspase-1。 IL-1和IL-18分别在炎症和Th2偏斜中很重要。冷冻蛋白对于介导加剧炎症的巨噬细胞坏死也很重要。因此，有令人信服的理由相信Monarch-1和冷冻蛋白在哮喘中具有至关重要的作用，但是没有体内数据可以表明这种情况是这种情况。此外，我们已经表明，这两种蛋白质都是ATP结合蛋白，它们表现出ATPase活性，因此提供了调节其功能的方法，这可能是引起药物发现的重要导致。该提案的目标是：（1）研究君主-1在三种哮喘动物模型中的相关性（OVA诱导的，内毒素和房屋灰尘螨，并描述Monarch-1在体内和Ex ex Vivo中的生物化学效应。 Monarch-1和冷冻蛋白的核苷酸结合特性和ATPase功能。