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，以恢复组织完整性和体内平衡。虽然在宿主反应正常的情况下可以解决，但当一个关键的宿主因子失活、失调或遗传和/或环境因素共同导致慢性肺时，外源性损伤就不能被控制

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