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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Transition Award (R00)
Project #
4R00HL111151-03
Application #
8843119
Study Section
No Study Section (in-house review) (NSS)
Program Officer
Tigno, Xenia
Project Start
2014-08-01
Project End
2017-07-31
Budget Start
2014-08-01
Budget End
2015-07-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Duke University
Department
Type
DUNS #
City
Durham
State
NC
Country
United States
Zip Code
27705
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Ito, Yoko; Schaefer, Niccolette; Sanchez, Amelia et al. (2018) Toll-Interacting Protein, Tollip, Inhibits IL-13-Mediated Pulmonary Eosinophilic Inflammation in Mice. J Innate Immun 10:106-118
Lugogo, Njira; Francisco, Dave; Addison, Kenneth J et al. (2018) Obese asthmatic patients have decreased surfactant protein A levels: Mechanisms and implications. J Allergy Clin Immunol 141:918-926.e3
Kummarapurugu, Apparao B; Zheng, Shuo; Ledford, Julie et al. (2018) High-Mobility Group Box 1 Upregulates MUC5AC and MUC5B Expression in Primary Airway Epithelial Cells. Am J Respir Cell Mol Biol 58:126-128
Addison, Kenneth J; Morse, John; Robichaud, Annette et al. (2017) A Novelin vivoSystem to Test Bronchodilators. J Infect Pulm Dis 3:
Noutsios, George T; Willis, Amanda L; Ledford, Julie G et al. (2017) Novel role of surfactant protein A in bacterial sinusitis. Int Forum Allergy Rhinol 7:897-903
Hsia, Bethany J; Ledford, Julie G; Potts-Kant, Erin N et al. (2016) Correction notice for TNF-R on mast cells regulate airway responses to Mycoplasma pneumoniae. J Allergy Clin Immunol 137:336
Huang, C; Jiang, D; Francisco, D et al. (2016) Tollip SNP rs5743899 modulates human airway epithelial responses to rhinovirus infection. Clin Exp Allergy 46:1549-1563
Stein, Michelle M; Hrusch, Cara L; Gozdz, Justyna et al. (2016) Innate Immunity and Asthma Risk in Amish and Hutterite Farm Children. N Engl J Med 375:411-421
Ledford, Julie G; Voelker, Dennis R; Addison, Kenneth J et al. (2015) Genetic variation in SP-A2 leads to differential binding to Mycoplasma pneumoniae membranes and regulation of host responses. J Immunol 194:6123-32

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