Increased airway smooth muscle mass, due either to hypertrophy or hyperplasia, is present in patients with asthma. While the biochemical pathways regulating cell proliferation have been well studied, little is known about the biochemical pathways regulating airway smooth muscle protein synthesis, cell size or the accumulation of contractile apparatus proteins. Recent data from cell culture models and patients with asthma suggest that airway smooth muscle contractile protein expression may be regulated in a post- transcriptional manner. In this revised application, we propose that airway smooth muscle hypertrophy requires the activation of specific translational control pathways. To test this, we will study 1) a cell culture model of hypertrophy in which primary human bronchial smooth muscle cells are treated with transforming growth factor (TGF)-beta; 2) two mouse models of asthma; and 3) biopsy samples from human asthmatics. We propose three Specific Aims:
Specific Aim 1. Determine the contributions of contractile apparatus transcription and translation in the development of human airway smooth muscle hypertrophy. We hypothesize that: 1) TGFbeta promotes airway smooth muscle hypertrophy by increasing both gene transcription and translational efficiency; and 2) murine airway remodeling is characterized in part by smooth muscle hypertrophy.
Specific Aim 2. Examine the contribution of cap-dependent protein synthesis to human airway smooth muscle hypertrophy. We hypothesize that: 1) 4E-BP phosphorylation, which increases the availability of elF4E for elF4F complex formation, is required for TGFbeta-induced airway smooth muscle hypertrophy; 2) elF4E phosphorylation by MAP kinase signal integrating kinase (MNK)-1 is required for airway smooth muscle hypertrophy; and 3) airway remodeling is characterized in part by increased phosphorylation of airway smooth muscle 4E-BP and elF4E.
Specific Aim 3. Examine the contribution of cap-independent protein synthesis to human airway smooth muscle hypertrophy. We hypothesize that: 1) p70 ribosomal S6 kinase (S6 kinase) is neither required nor sufficient for airway smooth muscle hypertrophy; 2) GSK3beta phosphorylation and inactivation is required and sufficient for airway smooth muscle hypertrophy; and 3) airway remodeling is characterized in part by increased phosphorylation of airway smooth muscle GSK3beta. Understanding biochemical mechanisms of airway remodeling in asthma will lead to improvements in the treatment of this disease. ? ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
1R01HL079339-01A2
Application #
7146950
Study Section
Lung Cellular, Molecular, and Immunobiology Study Section (LCMI)
Program Officer
Banks-Schlegel, Susan P
Project Start
2006-07-24
Project End
2011-06-30
Budget Start
2006-07-24
Budget End
2007-06-30
Support Year
1
Fiscal Year
2006
Total Cost
$358,860
Indirect Cost
Name
University of Michigan Ann Arbor
Department
Pediatrics
Type
Schools of Medicine
DUNS #
073133571
City
Ann Arbor
State
MI
Country
United States
Zip Code
48109
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
Whiteman, Eileen L; Fan, Shuling; Harder, Jennifer L et al. (2014) Crumbs3 is essential for proper epithelial development and viability. Mol Cell Biol 34:43-56
Anyanwu, Anuli C; Bentley, J Kelley; Popova, Antonia P et al. (2014) Suppression of inflammatory cell trafficking and alveolar simplification by the heme oxygenase-1 product carbon monoxide. Am J Physiol Lung Cell Mol Physiol 306:L749-63
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
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
Naik, Payal K; Bozyk, Paul D; Bentley, J Kelley et al. (2012) Periostin promotes fibrosis and predicts progression in patients with idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 303:L1046-56
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
Bozyk, Paul D; Popova, Antonia P; Bentley, John Kelley et al. (2011) Mesenchymal stromal cells from neonatal tracheal aspirates demonstrate a pattern of lung-specific gene expression. Stem Cells Dev 20:1995-2007
Deng, Huan; Hershenson, Marc B; Lei, Jing et al. (2010) p70 Ribosomal S6 kinase is required for airway smooth muscle cell size enlargement but not increased contractile protein expression. Am J Respir Cell Mol Biol 42:744-52

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