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.

支原体肺炎（MP）经常在慢性哮喘患者的气道上定居，被认为是 对哮喘加重的贡献。表面活性剂蛋白A（SP-A）在还原方面具有良好的功能 细菌感染，但其在慢性肺部疾病（例如哮喘）中的作用不太明确。我以前的 工作表明，与WT相比，缺乏SP-A的小鼠在MP感染期间的气道收缩增加 小鼠和抑制TNF-转录可以减少其反应。另外，小鼠缺乏SP-A 在过敏/感染模型（OVA+MP）中具有增强的感染和气道收缩并抑制 MP感染之前的TNF-¿转录也可以使SP-A - / - 过敏小鼠的气道反应性降低到水平 在WT过敏小鼠中测量。目前尚不清楚MP是否与肺肥大细胞相互作用和原因 激活/脱粒，如果SP-A在保护MP刺激中起作用，从而保护了MP刺激 由于潜在释放有害产品而导致损坏的气道。因此，中心假设 测试的是，由SP-A调节的肥大细胞-TNF-相互作用在MP诱导的 在感染过程中加剧，因此，如果SP-A降低，没有或功能失调，则 同时发生的MP感染后，过敏性肺部环境将被遗忘。提出的研究将有助于 阐明1）SP-A介导TNF-生产和肥大细胞反应的机制 MP感染； 2）肥大细胞和嗜酸性粒细胞的作用及其在MP中的各自贡献 感染过敏性气道（OVA + MP）和3）从哮喘患者与肺部分离的SP-A功能 来自正常的sp-a在调节肥大细胞和嗜酸性粒细胞反应中。 MP感染将以双重检查 敲除小鼠先天缺乏肥大细胞和SP-A（kitw-sh/w-shsp-a - / - ）或嗜酸性粒细胞和sp-a （philtgsp-a - / - ）在非过敏性和过敏性气道中。我的主要职业目标是获得终身职位 并在主要的生物医学机构建立独立的研究实验室。我的长期职业目标 是领导一个与研究生和毕业后合作的实验室，我可以为 了解肺宿主防御感染和非感染药物。为了实现这些目标，我 将发展我的智力知识基础，增强我的领导能力并增强必要的 在拟议的研究的整个过程中，技术技能。有价值的培训很容易在 Wright Lab和我的联合官员的实验室。卡夫和肺部医学系的福斯特 在杜克大学，以及我参与的其他出色合作者。促进和加强 我在奖励期间的进步，我组织了一个公认的科学家咨询委员会 以及我应用不同领域的专家。拟议的研究集体将 增强我们对SP-A在肺中的免疫保护机械作用的理解，并可能导致 在持续的MP感染的慢性哮喘患者的更好治疗方案中。