Antonia P. Popova, M.D., a pediatric pulmonologist, is focusing her career on bronchopulmonary dysplasia (BPD), a chronic lung disease of prematurely-born infants. During her fellowship, Dr. Popova published 4 papers on BPD and lung mesenchymal stromal cells. During the proposed training, Dr. Popova will continue work with her Mentor, Marc Hershenson, and receive additional scientific direction from Co-Mentor Stephen Weiss, an expert in matrix biology. However, her main goal will to be to acquire skills needed to become an independent investigator in the conduct of patient-oriented research, and to translate basic discoveries to the clinical problem of BPD. To achieve this, Dr. Popova will enroll in the School of Public Health Clinical Research Masters Program and receive additional mentorship from Dr. Fernando Martinez, an established pulmonary clinical investigator. She will also take coursework in computational medicine and bioinformatics under the supervision of a third Co-Mentor, Dr. Santiago Schnell. Dr. Popova's general hypothesis is that mesenchymal stromal cell myofibroblastic differentiation and matricellular protein expression play critical roles in BPD pathogenesis. To test this, she proposes the three Specific Aims, each of which is paired with Specific Training Objectives: 1. Measure the gene expression of lung mesenchymal stromal cells, focusing on matricellular proteins. Specific hypothesis: Mesenchymal stromal cells maintain a stable phenotype of myofibroblastic differentiation that is coupled with matricellular protein expression. Tracheal aspirates of premature infants will be examined for matricellular protein expression and mesenchymal stromal cells. Stromal cell mRNA and protein expression will be measured by microarray and ELISA/immunoblotting. Training Objective: Develop experience and understanding in experimental design, informed consent, and management of a research team. 2. Correlate neonatal lung mesenchymal stromal cell matricellular protein expression with clinical outcomes. Specific hypothesis: Expression of the matricellular proteins predicts BPD development. Relative odds of BPD as a function of tracheal aspirate protein expression and mesenchymal stromal cell gene expression will be calculated using multivariate regression analysis. Training Objectives: Acquire experience and understanding in the areas of experimental design, statistics, computational medicine and bioinformatics. 3. Examine expression and localization of matricellular proteins in the lungs of premature infants. Specific hypothesis: Matricellular protein expression is increased in the lungs of infants with BPD. Using University of Rochester neonatal lung biorepository samples, matricellular protein expression will be assessed by laser capture microscopy, qPCR and stereology-based quantitative immunohistochemisty. Training Objective: Acquire experience/expertise in methods used to quantify gene expression in small samples of human tissue. Completion of this work will provide insight into the origins of BPD and provide training for Dr. Popova, facilitating her transition to independent investigator in patient-oriented research.

Public Health Relevance

This application seeks to train Antonia P. Popova MD in the methods and approaches needed to perform patient-oriented research in pediatric pulmonology. Specifically, Dr. Popova will focus on bronchopulmonary dyplasia (BPD), a chronic lung disease of premature infants which is an increasingly common cause of childhood asthma. The proposed training program, which includes coursework in the School of Public Health Clinical Research Masters Program and University of Michigan Center for Computational Medicine and Bioinformatics, will enable Dr. Popova to become an independent investigator, and ultimately improve health outcomes in premature infants.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Mentored Patient-Oriented Research Career Development Award (K23)
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Special Emphasis Panel (ZHL1-CSR-X (M1))
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Colombini-Hatch, Sandra
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University of Michigan Ann Arbor
Schools of Medicine
Ann Arbor
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Cui, Tracy X; Maheshwer, Bhargavi; Hong, Jun Y et al. (2016) Hyperoxic Exposure of Immature Mice Increases the Inflammatory Response to Subsequent Rhinovirus Infection: Association with Danger Signals. J Immunol 196:4692-705
Popova, Antonia P; Cui, Tracy X; Kaciroti, Niko et al. (2015) Tracheal Aspirate Levels of the Matricellular Protein SPARC Predict Development of Bronchopulmonary Dysplasia. PLoS One 10:e0144122
Popova, Antonia P; Bentley, J Kelley; Cui, Tracy X et al. (2014) Reduced platelet-derived growth factor receptor expression is a primary feature of human bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 307:L231-9
Bentley, J Kelley; Chen, Qiang; Hong, Jun Young et al. (2014) Periostin is required for maximal airways inflammation and hyperresponsiveness in mice. J Allergy Clin Immunol 134:1433-1442
Popova, Antonia P (2013) Mechanisms of bronchopulmonary dysplasia. J Cell Commun Signal 7:119-27
Bozyk, Paul D; Bentley, J Kelley; Popova, Antonia P et al. (2012) Neonatal periostin knockout mice are protected from hyperoxia-induced alveolar simplication. PLoS One 7:e31336
Popova, Antonia P; Bentley, J Kelley; Anyanwu, Anuli C et al. (2012) Glycogen synthase kinase-3?/?-catenin signaling regulates neonatal lung mesenchymal stromal cell myofibroblastic differentiation. Am J Physiol Lung Cell Mol Physiol 303:L439-48