Environmental Chitin Exposure in the Pathogenesis of Asthma

描述(申请人提供)：哮喘是一种慢性炎症性疾病，深刻影响受影响个人的生活质量，并给国家医疗保健系统带来沉重负担。为了减少哮喘的患病率，需要更多地了解环境因素引发呼吸道病理变化的机制。暴露于常见环境过敏原以及对屋尘螨、真菌孢子和蟑螂的呼吸道过敏是哮喘发生的危险因素。甲壳素是这些刺激物中常见的一种，因为它存在于节肢动物的外骨骼、甲壳类动物的壳和真菌的细胞壁中。甲壳素是地球上含量第二丰富的聚合物，是N-乙酰氨基葡萄糖的线性聚合物。在最近的工作中，小鼠暴露在甲壳素颗粒中，诱导了与过敏相关的免疫细胞的积累。哺乳动物几丁质酶和几丁质酶样蛋白在哮喘患者中升高，并与过敏性炎症有关。这些事实提出了这样一种可能性，即环境中接触甲壳素是哮喘发病的关键因素。然而，甲壳素被天然免疫系统识别的机制还不是很清楚，还需要进一步研究几丁质暴露在哮喘发病机制中的作用。这项建议的科学目标是研究几丁质在呼吸道中的识别机制，并了解几丁质暴露在哮喘发生发展中的作用。为了实现这一目标，我们将创建定义的N-乙酰氨基葡萄糖低聚糖来探测和确定天然免疫系统细胞(如巨噬细胞和上皮细胞)识别的最小链长。我们还将使用哮喘小鼠模型和体外细胞共培养方法来确定几丁质在呼吸道中的炎症反应的细胞成分。最后，我们将在哮喘小鼠模型中研究甲壳素暴露如何影响随后使用过敏原特异性转基因T细胞启动过敏原特异性T细胞。其具体目的是：(1)确定介导甲壳素识别和复制对甲壳素的炎症反应的寡糖；(2)阐明甲壳素暴露的上皮细胞或者激活肺泡巨噬细胞的作用；(3)在哮喘真菌模型中确定甲壳素暴露在极化过敏原特异性T细胞反应中的作用。从培训的角度来看，这项工作将在以下环境中进行：1)充满活力和活力的赞助商实验室，2)强大的环境毒理学机构培训计划，3)研究哮喘基础和临床科学的全国最强的研究环境之一，从而培养与其他哮喘研究人员进行科学互动的机会，以及4)与可通过美国哮喘基金会进行培训的智力资源和研究中心密切合作。

DESCRIPTION (provided by applicant): Asthma is a chronic inflammatory disease that profoundly impacts the quality of life of affected individuals and heavily burdens the national health care system. To reduce the prevalence of asthma, a greater understanding of the mechanisms by which environmental factors trigger pathological changes in the airway is needed. Exposure to common environmental allergens along with respiratory allergies to house dust mites, fungal spores, and cockroaches are risk factors in the development of asthma. Chitin is a common thread among these irritants, since it is present in the exoskeleton of arthropods, the shells of crustaceans, and the cell wall of fungi. Chitin, which is the second most abundant polymer on our planet, is a linear polymer of N- acetylglucosamine. In recent work, exposure of mice to chitin particles induced the accumulation of immune cells associated with allergy. Mammalian chitinases and chitinase-like proteins are elevated in individuals with asthma and have been implicated in allergic inflammation. These facts raise the possibility that environmental exposure to chitin is a key factor in the pathogenesis of asthma. However, the mechanism by which chitin is recognized by the innate immune system is not well established and further study of the role of chitin exposure in the pathogenesis of asthma is needed. The scientific goal of this proposal is to investigate the mechanisms of chitin recognition in the airway and to understand the role of chitin exposure in the development of asthma. To achieve this goal, we will create defined N-acetylglucosamine oligosaccharides to probe and determine the minimal chain length that is recognized by cells of the innate immune system such as macrophages and epithelial cells. We will also define the cellular components of the inflammatory response to chitin in the airway using mouse models of asthma and in vitro cell co-culture methods. Finally, we will examine how exposure to chitin influences the subsequent priming of allergen specific T-cells using allergen specific transgenic T-cells in a mouse model of asthma. The specific aims are to: (1) define the oligosaccharide that mediates recognition of chitin and reproduces the inflammatory response to chitin, (2) elucidate the role of chitin-exposed epithelial cells alternatively activating alveolar macrophages and (3) identify the role of chitin exposure in polarizing allergen specific T-cell responses in a fungal model of asthma. From a training standpoint, this work will be pursued in an environment characterized by: 1) an vibrant, dynamic sponsor's laboratory, 2) a strong institutional training program in environmental toxicology, 3) a research setting that is among the strongest in the nation for studying the basic and clincal science of asthma, thereby fostering many opportunities for scientific interactions with other asthma investigators, and 4) a close alliance with the intellectual resources and research cores available for training through the American Asthma Foundation.