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）：肺炎支原体（Mp）经常在慢性哮喘患者的气道中定殖，并被认为会导致哮喘恶化。表面活性蛋白 A (SP-A) 在减少细菌感染方面具有明确的功能，但其 在哮喘等慢性肺部疾病中的作用尚不明确。我之前的工作表明，与 WT 小鼠相比，缺乏 SP-A 的小鼠在 Mp 感染期间气道收缩增加，并且对 TNF-α 的抑制作用增强。转录会降低它们的反应。此外，小鼠缺乏 SP-A 在过敏/感染模型 (Ova+Mp) 中增强炎症和气道收缩，并抑制 TNF-α Mp 感染之前的转录也可以将 SP-A-/- 过敏小鼠的气道反应性减弱至 WT 过敏小鼠中测量的水平。目前尚不清楚 Mp 是否与肺肥大细胞相互作用并引起激活/脱颗粒，以及 SP-A 是否在保护免受 Mp 刺激方面发挥作用，从而保护气道免受潜在释放的有害产物造成的损害。因此，测试的中心假设是肥大细胞-TNF-？由 SP-A 调节的相互作用在感染期间 Mp 诱导的病情加重中发挥着至关重要的作用，因此，如果 SP-A 减少、缺失或功能失调，则并发 Mp 感染时过敏性肺环境的状况将会恶化。拟议的研究将有助于阐明 1) SP-A 介导 TNF-α 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对TNF-α的贡献在 Mp 感染的过敏性气道 (Ova + Mp) 中，以及 3) 从哮喘患者肺部分离的 SP-A 与从正常人分离的 SP-A 在调节肥大细胞和嗜酸性粒细胞反应方面的功能。将在先天性缺乏肥大细胞和 SP-A (KitW-sh/W-shSP-A-/-) 或嗜酸性粒细胞和 SP-A (PhilTgSP-A-/-) 的非过敏性双敲除小鼠中检查 Mp 感染和过敏性呼吸道。我的主要职业目标是获得终身教职并在一家大型生物医学机构建立一个独立的研究实验室。我的长期职业目标是领导一个实验室，与 作为研究生和博士后，我可以为理解肺宿主防御感染性和非感染性病原体做出贡献。为了实现这些目标，我将在整个拟议研究期间发展我的智力知识基础，加强我的领导技能，并提高必要的技术技能。赖特实验室和我的合作导师 Drs. 的实验室随时提供有价值的培训。来自杜克大学肺科的克拉夫特和福斯特，以及我所聘用的其他优秀合作者。为了促进和加强我在获奖期间的进步，我组织了一个由在我的应用的不同领域拥有专业知识的知名科学家和临床医生组成的咨询委员会。总的来说，拟议的研究将增强我们对 SP-A 在肺部的免疫保护机制作用的理解，并可能为患有持续性 Mp 感染的慢性哮喘患者提供更好的治疗选择。