Human studies suggest that retinol therapy in preterm infants ameliorates the morbid consequences of prematurity and conventional ventilation, which include alveolar simplification and subsequent chronic lung disease (CLD). Animal studies further reveal that retinol signaling regulates the processes that determine alveolar formation, but neither human nor animal studies have addressed the molecular mechanism by which either retinol amelioration or regulation occurs in CLD. Using a lamb model of prematurity, conventional ventilation, and subsequent alveolar simplification, we established that retinol therapy of conventionally ventilated preterm lambs (vitA+CV) permits alveolar formation that resembles the lungs of preterm lambs treated with continuous positive airway pressure (CPAP; preterm control), and term newborn lambs (gestation control). Furthermore, vitA+CV or CPAP treatment permits expression of surfactant protein B (SP-B), vascular endothelial growth factor (VEGF), and p53 (a marker of apoptosis) versus CV treatment. A major novel advancement by our group is that a specific RARa agonist stimulates normal alveolar formation in the face of conventional ventilation in our CLD model. Our focus on molecular mechanisms will be on vitamin A regulation of genes for SP-B (direct regulation), VEGF (indirect regulation), and p53 (indirect regulation). SP-B and VEGF are co-expressed by alveolar type II cells in the lung; p53 is expressed by mesenchyme. The overall hypothesis, tested by the following 3 specific aims, is that vitamin A therapy permits appropriate alveolar formation through the classical retinoid signaling pathway and results in both direct and indirect regulation of downstream gene products.
Specific Aim 1 will determine the rescue of alveolar formation by vitamin A in chronically ventilated preterm lambs.
Specific Aim 2 will compare CV with or without RAR/RXR agonists versus CPAP with or without RAR/RXR antagonists to identify mechanisms of action of vitamin A.
This aim will test the hypothesis that vitamin A signaling in our model occurs through RAR(/RXR.
Specific Aim 3 will identify the molecular mechanisms by which vitamin A impacts SP-B, VEGF, and p53 promoter function. We will use lung cells isolated from lambs to recapitulate the in vivo findings, and transient transfection of stable cell lines to isolate specific mechanisms. We will test the hypothesis that the promoter regions of our 3 target genes are retinoid responsive. Thus, this project will provide novel mechanistic insights about alveolar formation and its dysregulation in CLD.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL062875-07
Application #
7195693
Study Section
Lung Injury, Repair, and Remodeling Study Section (LIRR)
Program Officer
Blaisdell, Carol J
Project Start
1999-09-01
Project End
2010-02-28
Budget Start
2007-03-01
Budget End
2008-02-29
Support Year
7
Fiscal Year
2007
Total Cost
$309,529
Indirect Cost
Name
University of Utah
Department
Pediatrics
Type
Schools of Medicine
DUNS #
009095365
City
Salt Lake City
State
UT
Country
United States
Zip Code
84112
Song, Yong; Dahl, MarJanna; Leavitt, Wendy et al. (2018) Vitamin A Protects the Preterm Lamb Diaphragm Against Adverse Effects of Mechanical Ventilation. Front Physiol 9:1119
Staub, Eveline; Dahl, Mar Janna; Yost, Calan et al. (2017) Preterm birth and ventilation decrease surface density of glomerular capillaries in lambs, regardless of postnatal respiratory support mode. Pediatr Res 82:93-100
Sutherland, Megan R; Ryan, Danica; Dahl, Mar Janna et al. (2016) Effects of preterm birth and ventilation on glomerular capillary growth in the neonatal lamb kidney. J Hypertens 34:1988-97
Abdullah, Osama M; Seidel, Thomas; Dahl, MarJanna et al. (2016) Diffusion tensor imaging and histology of developing hearts. NMR Biomed 29:1338-49
Joss-Moore, Lisa A; Hagen-Lillevik, Synneva J; Yost, Calan et al. (2016) Alveolar formation is dysregulated by restricted nutrition but not excess sedation in preterm lambs managed by noninvasive support. Pediatr Res 80:719-728
Joss-Moore, Lisa A; Lane, Robert H; Albertine, Kurt H (2015) Epigenetic contributions to the developmental origins of adult lung disease. Biochem Cell Biol 93:119-27
Albertine, Kurt H (2015) Utility of large-animal models of BPD: chronically ventilated preterm lambs. Am J Physiol Lung Cell Mol Physiol 308:L983-L1001
Hamvas, Aaron; Deterding, Robin; Balch, William E et al. (2014) Diffuse lung disease in children: summary of a scientific conference. Pediatr Pulmonol 49:400-9
Null, Donald M; Alvord, Jeremy; Leavitt, Wendy et al. (2014) High-frequency nasal ventilation for 21 d maintains gas exchange with lower respiratory pressures and promotes alveolarization in preterm lambs. Pediatr Res 75:507-16
Joss-Moore, Lisa; Carroll, Travis; Yang, Yan et al. (2013) Intrauterine growth restriction transiently delays alveolar formation and disrupts retinoic acid receptor expression in the lung of female rat pups. Pediatr Res 73:612-620

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