Environmental Chitin Exposure in the Pathogenesis of Asthma

描述（由申请人提供）：哮喘是一种慢性炎症性疾病，严重影响受影响个体的生活质量，并给国家卫生保健系统带来沉重负担。为了降低哮喘的患病率，需要更深入地了解环境因素触发气道病理变化的机制。 暴露于常见的环境过敏原沿着对室内尘螨、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的常见物质，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。甲壳素是我们星球上第二丰富的聚合物，是N-乙酰葡糖胺的线性聚合物。在最近的工作中，小鼠暴露于甲壳素颗粒诱导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。这些事实提高了环境暴露于几丁质是哮喘发病机制中的关键因素的可能性。然而，甲壳素被先天免疫系统识别的机制还没有很好地建立，需要进一步研究甲壳素暴露在哮喘发病机制中的作用。 这项计划的科学目标是研究呼吸道中几丁质识别的机制，并了解几丁质暴露在哮喘发展中的作用。为了实现这一目标，我们将创建定义的N-乙酰葡糖胺寡糖，以探测和确定先天免疫系统细胞（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气道中对几丁质的炎症反应的细胞成分。最后，我们将研究暴露于甲壳素如何影响随后的过敏原特异性T细胞的过敏原特异性转基因T细胞在哮喘小鼠模型中的启动。具体目标是：（1）确定介导几丁质识别和再现对几丁质的炎症反应的寡糖，（2）阐明几丁质暴露的上皮细胞交替激活肺泡巨噬细胞的作用，和（3）鉴定几丁质暴露在哮喘真菌模型中极化过敏原特异性T细胞反应中的作用。 从培训的角度来看，这项工作将在具有以下特点的环境中进行：1）一个充满活力，充满活力的申办者的实验室，2）一个强大的环境毒理学机构培训计划，3）一个研究环境，是在全国最强的研究哮喘的基础和临床科学，从而促进与其他哮喘研究人员的科学互动的许多机会，和4）通过美国哮喘基金会与可用于培训的智力资源和研究核心紧密联盟。 公共卫生相关性：哮喘是一种慢性疾病，严重降低生活质量，给国家卫生系统带来沉重负担。该提案的科学目的是研究环境暴露于甲壳素的作用，甲壳素存在于环境中的昆虫，甲壳类动物和霉菌孢子中，在哮喘的发展中。这些研究的结果将有助于确定新的治疗靶点，从而在哮喘发展的早期进行临床干预。

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. PUBLIC HEALTH RELEVANCE: Asthma is a chronic disease that significantly reduces quality of life and places a large burden on the national health system. The scientific purpose of this proposal is to study the role of environmental exposure to chitin, which is found in the environment in insects, crustaceans, and mold spores, in the development of asthma. The results of these investigations will help to identify new therapeutic targets allowing clinical interventions early in the development of asthma.