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: 8532970
• 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/8532970
• 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（由申请方提供）：肺炎支原体（Mp）经常定植于慢性哮喘患者的气道，并被认为有助于哮喘的恶化。表面活性剂蛋白A（SP-A）在减少细菌感染方面具有公认的功能，但其 在慢性肺部疾病，如哮喘中的作用还不太清楚。我以前的工作表明，小鼠缺乏SP-A增加气道收缩在MP感染相比，野生型小鼠和抑制TNF-？转录降低了它们的反应。此外，缺乏 SP-A在过敏/感染模型（Ova+MP）中增强了炎症和气道收缩，并抑制了TNF-？在Mp感染之前转录的蛋白质也可以将SP-A-/-过敏小鼠中的气道反应性减弱到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活化/脱粒，以及SP-A是否在保护免受MP刺激中起作用，从而保护气道免受由于有害产物的潜在释放而造成的损害。因此，中心假设测试是肥大细胞TNF-？由SP-A调节的相互作用在感染期间MP诱导的恶化中起关键作用，因此，如果SP-A减少、缺失或功能障碍，则过敏性肺环境中的病症将在并发MP感染时恶化。这项研究将有助于阐明1）SP-A介导TNF-？生产和肥大细胞的反应，在MP感染; 2）肥大细胞和嗜酸性粒细胞的作用和各自的贡献TNF-？3）哮喘患者肺组织中分离的SP-A与正常人肺组织中分离的SP-A在调节肥大细胞和嗜酸性粒细胞反应中的功能。将在非过敏性和过敏性气道中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-/-）的双敲除小鼠中检查MP感染。我的主要职业目标是获得终身职位，并在一家主要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， 作为研究生和博士后，我可以为理解肺宿主对感染性和非感染性病原体的防御做出贡献。为了实现这些目标，我将在整个拟议研究期间发展我的知识基础，加强我的领导技能，并提高必要的技术技能。在赖特实验室和我的合作导师、杜克大学肺医学系的Kraft博士和Foster博士的实验室，以及我聘请的其他优秀合作者的实验室，都可以随时获得有价值的培训。为了在获奖期间促进和支持我的进步，我组织了一个由在我的申请的不同领域具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，拟议的研究将提高我们对SP-A在肺中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。

项目成果

Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses.

• DOI: 10.4049/jimmunol.1500104
• 发表时间: 2015-06-15
• 期刊: Journal of immunology (Baltimore, Md. : 1950)
• 作者: Ledford JG;Voelker DR;Addison KJ;Wang Y;Nikam VS;Degan S;Kandasamy P;Tanyaratsrisakul S;Fischer BM;Kraft M;Hollingsworth JW
• 通讯作者: Hollingsworth JW

A Novel in vivo System to Test Bronchodilators.

• DOI: 10.16966/2470-3176.120
• 发表时间: 2017-03
• 期刊: Journal of infectious pulmonary diseases
• 作者: Addison KJ;Morse J;Robichaud A;Daines MO;Ledford JG
• 通讯作者: Ledford JG

Identification and Quantitation of Coding Variants and Isoforms of Pulmonary Surfactant Protein A.

• DOI: 10.1021/pr500307f
• 发表时间: 2014-08-01
• 期刊: JOURNAL OF PROTEOME RESEARCH
• 影响因子: 4.4
• 作者: Foster, Matthew W.;Thompson, J. Will;Ledford, Julie G.;Dubois, Laura G.;Hollingsworth, John W.;Francisco, Dave;Tanyaratsrisakul, Sasipa;Voelker, Dennis R.;Kraft, Monica;Moseley, M. Arthur;Foster, W. Michael
• 通讯作者: Foster, W. Michael

Correction notice for TNF-R on mast cells regulate airway responses to Mycoplasma pneumoniae.

肥大细胞上的 TNF-R 调节气道对肺炎支原体反应的修正通知。

• DOI: 10.1016/j.jaci.2015.09.049
• 发表时间: 2016
• 期刊: The Journal of allergy and clinical immunology
• 作者: Hsia,BethanyJ;Ledford,JulieG;Potts-Kant,ErinN;Nikam,VinayakS;Lugogo,NjiraL;Foster,WMichael;Kraft,Monica;Abraham,SomanN;Wright,JoRae
• 通讯作者: Wright,JoRae