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

肺炎支原体(MP)经常定植于慢性哮喘患者的呼吸道，被认为是 导致哮喘加重。表面活性蛋白A(SP-A)具有广泛的还原功能 但它在哮喘等慢性肺部疾病中的作用还不是很清楚。我的前辈 研究表明，与WT相比，缺乏SP-A的小鼠在MP感染期间呼吸道收缩增加 而抑制肿瘤坏死因子转录则会降低它们的反应。此外，SP-A缺乏的小鼠 在过敏/感染模型(OVA+MP)中增强炎症和气道收缩，并抑制 肺炎支原体感染前的肿瘤坏死因子转录也可使SP-A-/-过敏性小鼠的气道反应性降低到 在WT过敏小鼠身上测量。目前尚不清楚MP是否与肺肥大细胞相互作用并导致 激活/脱颗粒以及SP-A是否起到保护MP刺激的作用，从而保护 避免航空公司因可能释放有害产品而受到损害。因此，中心假说 实验证明，肥大细胞-肿瘤坏死因子-β的相互作用受SP-A的调节，在MP诱导的过程中起着关键作用 在感染过程中恶化，因此，如果SP-A减少、缺失或功能障碍， 肺炎支原体并发感染可加重过敏性肺环境。建议的研究将有助于 阐明1)SP-A介导肿瘤坏死因子-β产生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在MP中的作用及各自对肿瘤坏死因子的贡献 感染的过敏性呼吸道(OVA+MP)和3)从哮喘患者肺中分离的SP-A的功能 SP-A在调节肥大细胞和嗜酸性粒细胞反应中的作用。MP感染将分两次进行检查 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-/-)在非过敏和过敏性呼吸道。我的主要职业目标是获得终身教职的职位 并在一家大型生物医学机构建立独立的研究实验室。我的长期职业目标 是领导一个实验室，在那里我可以与研究生和博士后合作，为 了解肺部宿主对感染性和非感染性病原体的防御。为了实现这些目标，我 将发展我的智力知识基础，加强我的领导能力，并提高必要的 在整个拟议研究期间掌握技术技能。有价值的培训随时可在 莱特实验室和我的共同导师，来自肺内科的克拉夫特和福斯特博士的实验室 在杜克大学，以及与我接触过的其他优秀合作者。促进和支撑 我的进展在获奖期间，我组织了一个由知名科学家组成的咨询委员会 以及在我的应用程序的不同领域拥有专业知识的临床医生。总的来说，拟议的研究将 提高对SP-A在肺组织中的免疫保护机制作用的认识(S) 为患有持续MP感染的慢性哮喘患者提供更好的治疗选择。

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.