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: 8881287
• 负责人: Julie Gunnells Ledford
• 金额: $ 23.43万
• 依托单位: UNIVERSITY OF ARIZONA
• 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 2017-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8881287
• 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; asthmatic; 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 (Mp) 经常在慢性哮喘患者的气道中定殖，并被认为 表面活性剂蛋白 A (SP-A) 具有明确的减少哮喘恶化的功能。 细菌感染，但其在哮喘等慢性肺部疾病中的作用尚不明确。 研究表明，与 WT 相比，缺乏 SP-A 的小鼠在 Mp 感染期间气道收缩增加 小鼠和 TNF-¿ 的抑制此外，缺乏 SP-A 的小鼠的反应也会减弱。 在过敏/感染模型 (Ova+Mp) 中增强炎症和气道收缩，并抑制 肿瘤坏死因子-¿ 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一定水平 在 WT 过敏小鼠中进行测量，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 因此，中心假设是由于有害产物的潜在释放而造成的损伤。 经测试，肥大细胞-TNF-¿由 SP-A 调节的相互作用在 Mp 诱导的过程中发挥着至关重要的作用 感染期间恶化，因此，如果 SP-A 减少、缺失或功能失调， 并发 Mp 感染时，过敏性肺部环境将会恶化。 研究建议将有助于缓解这种情况。 阐明 1) SP-A 介导 TNF-¿ 的机制生产和肥大细胞反应期间 Mp感染；2）肥大细胞和嗜酸性粒细胞的作用及其各自对TNF-¿在MP中 感染过敏性气道 (Ova + Mp) 和 3) 从哮喘患者肺部分离出的 SP-A 的功能与 正常人的 SP-A 在调节肥大细胞和嗜酸性粒细胞反应中的作用将进行双重检查。 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 的基因敲除小鼠 (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。 并在大型生物医学机构建立独立的研究实验室是我的长期职业目标。 是领导一个实验室，与研究生和博士后合作，我可以为 了解肺部宿主对感染性和非感染性病原体的防御。 将发展我的智力知识基础，增强我的领导技能，并增强必要的能力 在整个拟议研究期间，随时可以获得宝贵的培训。 赖特实验室以及我的合作导师肺科的卡夫博士和福斯特博士的实验室 杜克大学以及我所聘用的其他优秀合作者来促进和支持。 为了在奖励期间取得进展，我组织了一个由知名科学家组成的咨询委员会 总的来说，拟议的研究将在我的应用程序的不同领域具有强大的专业知识。 增强我们对 SP-A 在肺部的免疫保护机制作用的理解，并可能导致 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。