Environmental Chitin Exposure in the Pathogenesis of Asthma

环境甲壳素暴露与哮喘发病机制的关系

• 批准号: 8134862
• 负责人: Rene M Roy
• 金额: $ 2.91万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2013-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8134862
• 关键词: Accident and Emergency department; Acetylglucosamine; Affect; Air; Allergens; Allergic; Allergic inflammation; Alveolar Macrophages; American; Arthropods; Aspergillus; Asthma; Basophils; Binding; Breast; Cell Line; Cell Wall; Cells; Child; Chitin; Chitinase; Chronic; Chronic Disease; Clinical; Coculture Techniques; Crustacea; Cytokine Signaling; Data; Dendritic Cells; Development; Dictyoptera; Disease; Early treatment; Environment; Environmental Exposure; Environmental Irritants; Environmental Risk Factor; Epithelial Cells; Event; Exposure to; Extrinsic asthma; Fostering; Foundations; Fungal Spores; Generations; Glucosamine; Goals; Health system; Healthcare Systems; Hypersensitivity; IgE; Immune; Immune response; Immune system; In Vitro; Individual; Inflammatory; Inflammatory Response; Insecta; Interleukin-13; Investigation; Irritants; Laboratories; Length; Ligands; Lung; Macrophage Activation; Measures; Mediating; Methods; Modeling; Molds; Molecular; Mucous body substance; Mus; Oligosaccharides; Pathogenesis; Phenotype; Planets; Play; Polymers; Preparation; Prevalence; Production; Proteins; Proteomics; Public Health; Publishing; Pyroglyphidae; Quality of life; Recruitment Activity; Reporting; Reproduction spores; Research; Research Personnel; Resources; Risk Factors; Role; Science; Silicon Dioxide; Source; Stimulus; T cell response; T-Cell Receptor; T-Lymphocyte; Testing; Trachea; Training; Training Programs; Transgenic Mice; Transgenic Organisms; Visit; Work; base; cytokine; environmental allergen; environmental toxicology; exoskeleton; fungus; in vitro Assay; in vivo; macrophage; mouse model; new therapeutic target; particle; particle exposure; public health relevance; respiratory; response

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.

描述（由申请人提供）：哮喘是一种慢性炎症性疾病，对受影响个体的生活质量产生深远的影响，并为国家卫生保健系统负担重大。为了降低哮喘的患病率，对环境因素触发气道的病理变化的机制有更深入的了解。 暴露于常见的环境过敏原以及呼吸道过敏，以容纳尘螨，真菌孢子和蟑螂是哮喘发育的危险因素。几丁质是这些刺激物中的一个共同线，因为它存在于节肢动物的外骨骼中，甲壳类动物的壳和真菌的细胞壁。几丁质是我们行星上第二大大量聚合物，是N-乙酰葡萄糖的线性聚合物。在最近的工作中，小鼠暴露于几丁质颗粒会诱导与过敏相关的免疫细胞的积累。哮喘患者的哺乳动物几丁质酶和几丁质酶样蛋白升高，并与过敏性炎症有关。这些事实提出了一种可能性，即环境暴露是哮喘发病机理的关键因素。然而，尚无法确定有几丁质被天生免疫系统识别的机制，并且需要进一步研究几丁质暴露在哮喘发病机理中的作用。 该提案的科学目标是研究壳道在气道中识别的机制，并了解几丁质暴露在哮喘发育中的作用。为了实现这一目标，我们将创建定义的N-乙酰葡萄糖寡糖，以探测和确定由先天免疫系统（例如巨噬细胞和上皮细胞）识别的最小链长度。我们还将使用哮喘和体外细胞共培养方法的小鼠模型来定义气道中炎症反应的细胞成分。最后，我们将研究中几丁质的暴露如何使用过敏原特异性转基因T细胞在小鼠哮喘模型中使用过敏原特异性T细胞的后续启动。具体目的是：（1）定义介导的差异识别的寡糖并再现对几丁质的炎症反应，（2）阐明了几丁质蛋白暴露的上皮细胞的作用，可激活肺泡巨噬细胞，并确定奇数在极性变态化的拟合变化剂中的作用，并确定奇质暴露在拟合中。 从培训的角度来看，这项工作将在以下特征的环境中进行：1）充满活力的，动态的赞助商实验室，2）一个强大的机构培训计划，环境毒理学方面的强大机构培训计划，3）研究环境，该研究环境是全国最强的研究环境，是研究ASTHMA的基本和clincal科学的基本和clince互动的机会，从而促进了许多与其他研究员的互动，并与其他研究者进行了研究，并4）与其他研究员进行了研究，以及4）的研究环境，以及4），以及4）的研究环境，4）通过美国哮喘基金会进行培训。 公共卫生相关性：哮喘是一种慢性疾病，可大大降低生活质量，并承担国家卫生系统的巨大负担。该建议的科学目的是研究环境暴露于几丁质的作用，这在昆虫，甲壳类动物和霉菌孢子的环境中发现，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标，从而允许在哮喘发育初期进行临床干预。