SP-A as an immune modulator

SP-A 作为免疫调节剂

• 批准号: 8523176
• 负责人: Loretta G Que
• 金额: $ 135.82万
• 依托单位: DUKE UNIVERSITY
• 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 2016-02-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8523176
• 关键词: Allergens; Allergic; Allergic Disease; Allergic inflammation; Alveolar Macrophages; Animal Model; Antigens; Asthma; Attenuated; Bacterial Infections; Biochemical; Bronchoconstriction; Cells; Chronic lung disease; Defect; Environmental Irritants; Environmental Risk Factor; Epithelial; Epithelial Cells; Epithelium; Exposure to; Functional disorder; Genes; Genetic; Genetic Polymorphism; Genetic Variation; Genotype; Homeostasis; Host Defense Mechanism; Human; Immune; Immune response; Immune system; In Vitro; Infection; Inflammation; Injury; Integration Host Factors; Invaded; Knockout Mice; Lead; Link; Lung; Mechanics; Mediating; Membrane; Modeling; Mus; Mutation; Mycoplasma pneumoniae; Natural Immunity; Ovalbumin; Oxidants; Ozone; Patients; Phenotype; Physiological; Play; Pneumonia; Predisposition; Principal Investigator; Property; Proteins; Proteomics; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactant-Associated Proteins; Recombinants; Research Personnel; Resolution; Respiratory System; Respiratory tract structure; Role; Surface; Testing; Tissues; Variant; airway inflammation; asthmatic airway; base; cytokine; immunoregulation; in vivo; lung injury; macrophage; mouse model; oxidation; ozone exposure; pathogen; programs; response; success; therapy design; translational study

The fundamental roles of innate and adaptive host responses are to recognize and eradicate invading antigens, pathogens or altered self components to restore tissue integrity and homeostasis. While resolution can occur when the host response is normal, an exogenous insult cannot be contained when a critical host factor is inactivated, dysregulated, or genetic and/or environmental factors conspire to result in chronic lung disease. In our proposal, this critical host factor is surfactant protein A (SP-A), a protein that lines the epithelial surfaces in the lung. Normal SP-A can attenuate allergic inflammation, but SP-A that is altered or abnormal as a consequence of genetic polymorphisms and/or oxidative changes has abrogated ability to defend the host from environmental insults leading to excessive bronchoconstriction and allergic inflammation. Our preliminary studies in vitro, in animal models of airway inflammation and in patients with asthma have identified specific defects in the role of SP-A in the innate immune response that contribute to the persistence or exacerbation of asthma and allergic disease. The central hypothesis to be tested is that SP-A, which normally regulates innate immunity and protects the host from persistence and exacerbation of asthma, is dysfunctional in asthma. These projects will employ specific environmental challenges (infection and ozone exposure) to test the ability of SP-A to modulate allergic inflammation in asthma, and whether allelic variants of SP-A, insufficient quantities or oxidation are responsible for dysfunction of SP-A in asthma. Project 1 will evaluate the ability of human SP-A from asthmatic subjects and allelic variant SP-A to modulate the innate and adaptive responses to infection and ozone exposure, respectively, in the human macrophage and airway epithelial cell. Project 2 will employ murine models of ovalbumin sensitization and challenge to determine if asthmatic SP-A and allelic variants of SP-A effectively modulate inflammaton induced by an infectious challenge. Project 3 will determine whether a specific SP-A polymorphisms modulate differential sensitivity to ozone exposure in asthma (physiologic and mechanical), and whether SP-A itself undergoes oxidation during in vivo ozone exposure in human asthma.

先天性和适应性宿主反应的基本作用是识别和根除入侵的抗原、病原体或改变的自身成分，以恢复组织的完整性和稳态。虽然当宿主反应正常时可发生消退，但当关键宿主因子失活、失调或遗传和/或环境因素共同导致慢性肺损伤时，不能包含外源性损伤。 疾病在我们的建议中，这个关键的宿主因子是表面活性蛋白A（SP-A），一种排列在肺上皮表面的蛋白质。正常的SP-A可以减弱变应性炎症，但是由于遗传多态性和/或氧化变化而改变或异常的SP-A已经废除了保护宿主免受环境损伤的能力，导致过度的支气管收缩和变应性炎症。 炎症我们在体外、气道炎症动物模型和哮喘患者中的初步研究已经确定了SP-A在先天免疫应答中作用的特定缺陷，这些缺陷导致哮喘和过敏性疾病的持续或加重。待检验的中心假设是SP-A在哮喘中功能失调，SP-A通常调节先天免疫并保护宿主免于哮喘的持续和恶化。这些项目将采用特定的环境 挑战（感染和臭氧暴露），以测试SP-A调节哮喘中过敏性炎症的能力，以及SP-A的等位基因变体、数量不足或氧化是否是哮喘中SP-A功能障碍的原因。项目1将评估来自哮喘受试者的人SP-A和等位基因变体SP-A分别在人巨噬细胞和气道上皮细胞中调节对感染和臭氧暴露的先天性和适应性反应的能力。项目2将采用小鼠模型， 卵清蛋白致敏和攻击以确定哮喘SP-A和SP-A的等位基因变体是否有效地调节由感染性攻击诱导的炎症。项目3将确定特定SP-A多态性是否调节哮喘对臭氧暴露的不同敏感性（生理和机械），以及SP-A本身是否在人类哮喘体内臭氧暴露期间发生氧化。

项目成果

Asthma and the host-microbe interaction.

• DOI: 10.1016/j.jaci.2013.03.004
• 发表时间: 2013-05
• 期刊: JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
• 影响因子: 14.2
• 作者: Gilstrap, Daniel L.;Kraft, Monica
• 通讯作者: Kraft, Monica

SHP-1 as a critical regulator of Mycoplasma pneumoniae-induced inflammation in human asthmatic airway epithelial cells.

• DOI: 10.4049/jimmunol.1100573
• 发表时间: 2012-04-01
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Wang Y;Zhu Z;Church TD;Lugogo NL;Que LG;Francisco D;Ingram JL;Huggins M;Beaver DM;Wright JR;Kraft M
• 通讯作者: Kraft M