The role of SP-A in Mp-induced exacerbations during allergic airway disease.

SP-A 在过敏性气道疾病期间 Mp 诱导的恶化中的作用。

• 批准号: 8843119
• 负责人: Julie Gunnells Ledford
• 金额: $ 24.9万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-08-01 至 2015-02-27
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8843119
• 关键词: A Mouse; Acute; Advisory Committees; Affect; Air Pollutants; Allergens; Allergic; Alveolar; Area; Asthma; Attenuated; Award; Bacterial Infections; Binding; Biological Assay; Bronchoconstriction; Cell Degranulation; Cells; Child; Childhood; Chronic; Chronic Disease; Chronic lung disease; Collaborations; Data; Disease; Environment; Epithelial Cells; Fostering; Genetic Transcription; Goals; Host Defense; Immune; Infection; Inflammation; Inflammatory Response; Institution; Knockout Mice; Laboratory Research; Lead; Leadership; Lung; Measures; Mediating; Mentors; Microbe; Modeling; Mucous body substance; Mus; Mycoplasma pneumonia infection; Mycoplasma pneumoniae; Obstruction; Ovum; Play; Pneumonia; Positioning Attribute; Postdoctoral Fellow; Production; Pulmonary Surfactant-Associated Protein A; Pulmonary Surfactants; Pulmonology; Regulation; Research; Role; Scientist; Stimulus; Symptoms; TNF gene; Testing; Training; Universities; Walking; Work; airway hyperresponsiveness; airway inflammation; allergic airway disease; allergic response; base; career; constriction; cytokine; eosinophil; graduate student; killings; knowledge base; mast cell; response; skills

Mycoplasma pneumoniae (Mp) frequently colonizes the airways of chronic asthmatics and is thought to contribute to exacerbations of asthma. Surfactant protein A (SP-A) has well-established functions in reducing bacterial infections but its role in chronic lung diseases, such as asthma, is less well defined. My previous work shows that mice lacking SP-A have increased airway constriction during Mp infection compared to WT mice and that inhibition of TNF-¿ transcription reduces their responses. Additionally, mice deficient in SP-A have enhanced inflammation and airway constriction in an allergic/infection model (Ova+Mp) and inhibition of TNF-¿ transcription prior to Mp infection can also attenuate airway reactivity in SP-A-/- allergic mice to levels measured in WT allergic mice. It is not currently known if Mp interacts with pulmonary mast cells and causes activation/degranulation and if SP-A plays a role in protecting from Mp-stimulation, thereby protecting the airways from damage due to the potential release of harmful products. Therefore, the central hypothesis tested is that mast cell-TNF-¿ interactions, which are regulated by SP-A, play a crucial role in Mp-induced exacerbations during infection and therefore, if SP-A is decreased, absent or dysfunctional, conditions in the allergic lung environment will be worsened upon concurrent Mp infection. Research proposed will aide in elucidating 1) the mechanism by which SP-A is mediating TNF-¿ production and mast cell responses during Mp infection; 2) the role of mast cells and eosinophils and their respective contributions of TNF-¿ in Mp infected allergic airways (Ova + Mp) and 3) the functionality of SP-A isolated from lungs of asthmatics versus SP-A from normals in regulating mast cell and eosinophil responses. Mp infection will be examined in double knockout mice congenitally lacking both mast cells and SP-A (KitW-sh/W-shSP-A-/-) or eosinophils and SP-A (PhilTgSP-A-/-) in non-allergic and allergic airways. My primary career goal is to obtain a tenure-track position and establish an independent research laboratory at a major biomedical institution. My long-term career goal is to lead a lab where in collaboration with graduate students and post-docs, I can contribute to the understanding of lung host defense against infectious and noninfectious agents. To achieve these goals, I will develop my intellectual knowledge base, strengthen my leadership skills, and enhance the necessary technical skills throughout the duration of the proposed study. Valuable training is readily available in the Wright lab and in labs of my co-mentors, Drs. Kraft and Foster from the Department of Pulmonary Medicine at Duke University, as well as with the other excellent collaborators I have engaged. To promote and bolster my progress during the award period, I have organized an advisory committee of well-established scientists and clinicians with expertise in the different areas of my application. Collectively, the proposed research will enhance our understanding of the immuno-protective mechanistic role(s) of SP-A in the lung and may result in better treatment options for chronic asthmatics that suffer from persistent Mp infections.

肺炎支原体（Mycoplasma pneumoniae, Mp）经常在慢性哮喘患者的气道中定植，被认为是慢性哮喘的主要病原体