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: 8367002
• 负责人: Julie Gunnells Ledford
• 金额: $ 10.07万
• 依托单位: DUKE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-09-01 至 2014-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8367002
• 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

DESCRIPTION (provided by applicant): 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.

描述（由申请人提供）：支原体肺炎（MP）经常将慢性哮喘的气道定居，并被认为会导致哮喘的加剧。表面活性剂蛋白A（SP-A）在减少细菌感染方面具有良好的功能 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小鼠相比，缺乏SP-A的小鼠在MP感染过程中的气道收缩增加，并且抑制TNF-？转录减少了他们的反应。此外，小鼠缺乏 在过敏/感染模型（OVA+MP）和TNF-的抑制中，SP-A具有增强的炎症和气道收缩。在MP感染之前的转录还可以使SP-A - / - 过敏小鼠的气道反应性减少到WT过敏小鼠中测得的水平。目前尚不清楚MP是否与肺肥大细胞相互作用并引起激活/脱粒，并且SP-A是否在保护MP刺激中起作用，从而保护气道由于潜在释放有害产物而造成损害。因此，测试的中央假设是肥大细胞-TNF-？受SP-A调节的相互作用在感染期间在MP引起的加重中起着至关重要的作用，因此，如果SP-A减少，没有或功能失调，则在过敏性肺部环境中，MP感染后会恶化过敏性肺部环境。研究提出的研究将有助于阐明1）SP-A介导TNF-的机制？ MP感染期间的生产和肥大细胞反应； 2）肥大细胞和嗜酸性粒细胞的作用及其各自的TNF-贡献？在MP感染过敏性气道（OVA + MP）中，3）从哮喘患者的肺中分离出的SP-A功能，而SP-A与正常的SP-A在调节肥大细胞和嗜酸性粒细胞反应中的SP-A功能。在非过敏性和过敏性气道中，将在先天缺乏肥大细胞和SP-A（KITW-SH/W-SHSP-A - / - ）的双基因敲除小鼠中检查MP感染。我的主要职业目标是获得终身制职位，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之合作的实验室 研究生和博士后，我可以为对肺部宿主防御感染感染和非感染者的理解做出贡献。为了实现这些目标，我将发展我的知识知识基础，增强我的领导能力，并在整个拟议的研究期间增强必要的技术技能。在赖特实验室和我的联席会员博士的实验室中，很容易获得宝贵的培训。卡夫（Kraft）和杜克大学肺部医学系的福斯特（Foster）以及我参与的其他优秀合作者。为了在奖励期间促进和加强我的进步，我组织了一个咨询委员会，该咨询委员会在我的申请的不同领域中拥有专业知识的良好科学家和临床医生。总的来说，拟议的研究将增强我们对SP-A在肺中的免疫保护机械作用的理解，并可能为患有持续的MP感染的慢性哮喘患者提供更好的治疗选择。