The Role of the Major Alternaria Allergen Alt_a_1 in Airway Inflammation

主要链格孢过敏原 Alt_a_1 在气道炎症中的作用

基本信息

批准号：
8313847
负责人：
Christopher Brian Lawrence
金额：
$ 19.6万
依托单位：
VIRGINIA POLYTECHNIC INST AND ST UNIV
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-08-05 至 2013-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8313847
关键词：
Allergens Allergic Disease Allergic inflammation Alternaria Amino Acid Motifs Amino Acid Sequence Amino Acids Antigens Asthma Binding Biochemical Cell surface Cells Clinical Complex Country Development Disease Progression Employee Strikes Endocytosis Environment Environmental Risk Factor Epithelial Cells Etiology Event Exhibits Exposure to Extrinsic asthma Functional disorder Fungal Proteins Fungal Spores Goals Human Hypersensitivity IgE Immune Immune response Immune system Immunity In Vitro Individual Inflammatory Inflammatory Response Interleukin-13 Interleukin-4 Knock-out Knowledge Lead Life Liquid substance Lung Mediating Modeling Molecular Movement Mus Organism Pathogenesis Patients Phosphatidylinositols Phospholipids Play Prevalence Prevention Prevention strategy Property Proteins Recombinants Recurrence Reproduction spores Role Source Testing Th2 Cells airway hyperresponsiveness airway inflammation allergic airway disease base cell type clinically relevant cytokine design effective therapy esterase experience fungus in vivo innovation inositol 3-phosphate insight microbial mutant novel novel therapeutic intervention pathogen prevent response transcytosis uptake

项目摘要

DESCRIPTION (provided by applicant): The inflammatory airway response in asthma may be the result of immune cells that are dysregulated towards environmental factors such as airborne fungi. The long-term goal of this project is to better understand the pathophysiological mechanisms of Th2-type airway inflammation in asthma. Exposure to the fungus, Alternaria, has long been implicated in the development and exacerbation of human asthma. After intranasal exposure to Alternaria spores and individual proteins, naive mice exhibit marked eosinophilic airway inflammation, enhanced Th2 sensitization to innocuous antigens, and airway hyperreactivity. Despite the well-documented clinical importance of Alternaria in the development, onset, and exacerbation of allergic airway diseases such as asthma, little knowledge exists about the role of individual fungal products in these pathological states. The importance of and detailed mechanisms of allergen uptake and movement through the epithelial cell layer (endocytosis and transcytosis) have not been explored to any great extent. This innovative project focuses on the secreted major Alternaria allergen Alt_a_1. It will assess the role of Alt_a_1 in allergic disease by utilizing bronchoalveolar epithelial cells and murine models of airway inflammation. We have discovered that Alt_a_1 is proinflammatory and harbors a unique amino acid motif (RXLR) that facilitates binding to cell surface PI-3-P and cellular entry. In aim 1 the role of Alt_a_1 in innate and adaptive immune responses in vitro and in murine models of asthma will be investigated. The effects of recombinant Alt_a_1 protein and fungal knockout mutants lacking Alt_a_1 will be examined. In specific aim 2 the importance of the Alt_a_1's esterase activity and RXLR motif in cellular entry and immunological responses will be characterized. Recombinant Alt_a_1 will be used to define amino acid residues required for esterase activity, for PI-3-P binding, and for cellular entry. Epithelial cell immune responses following treatment with the Alt_a_1 proteins will be investigated. This project will lead to a better understanding of the mechanisms of persistent and recurrent airway inflammation and may lead to the development of more specific and effective therapies and prevention strategies, especially if PI-3-P-mediated cell entry proves of general importance to allergenicity.

描述（由申请人提供）：哮喘中的炎症气道反应可能是免疫细胞对环境因素（如空气传播真菌）失调的结果。该项目的长期目标是更好地了解哮喘中Th2型气道炎症的病理生理机制。长期以来，接触真菌，替代人，与人类哮喘的发展和加剧有关。鼻内暴露于替代孢子和单个蛋白质后，幼稚的小鼠表现出明显的嗜酸性气道炎症，对无害抗原的Th2敏化增强以及气道高反应性。尽管有据可查的替代性在发育，发作和加剧过敏性气道疾病（例如哮喘）中的临床重要性，但对这些病理状态中单个真菌产品的作用的知识很少。过敏原摄取和通过上皮细胞层运动（内吞和转胞吞作用）运动的重要性尚未在很大程度上探索。这个创新的项目着重于分泌的主要替代过敏原alt_a_1。它将通过利用支气管肺泡上皮细胞和气道炎症模型来评估ALT_A_1在过敏性疾病中的作用。我们已经发现Alt_A_1是促炎性的，并且拥有独特的氨基酸基序（RXLR），可促进与细胞表面PI-3-P和细胞进入的结合。在AIM 1中，将研究Alt_a_1在体外和哮喘鼠模型中的先天和适应性免疫反应中的作用。重组ALT_A_1蛋白质和缺乏Alt_A_1的真菌敲除突变体的影响。在特定的目标2中，将表征Alt_a_1的酯酶活性和RXLR基序在细胞进入和免疫反应中的重要性。重组ALT_A_1将用于定义酯酶活性，PI-3-P结合和细胞进入所需的氨基酸残基。将研究用Alt_A_1蛋白治疗后的上皮细胞免疫反应。该项目将更好地理解持续性和复发性气道炎症的机制，并可能导致开发更具体，有效的疗法和预防策略，尤其是如果PI-3-P介导的细胞入口证明对过敏性具有一般重要性。