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A Novel Approach to Prevent in Utero Nicotine Lung Injury

Institution: LA Biomedical Research Institute at Harbor-UCLA Medical Center
Investigator(s): Virender Rehan, M.D.
Award Cycle: 2008 (Cycle 17) Grant #: 17RT-0170 Award: $564,957
Subject Area: General Biomedical Science
Award Type: Research Project Awards

Initial Award Abstract
Maternal smoking during pregnancy not only poses significant immediate risks for the unborn fetus but also may have life long implications. It has broad adverse effects on fetal outcome, including increased risk of spontaneous abortion, stillbirth, low birth weight, early neonatal mortality, sudden infant death syndrome, and poor long-term pulmonary outcome. Although not widely appreciated, there is strong evidence for the deleterious effects on both prenatal and postnatal lung development following exposure to maternal smoke during pregnancy. And sadly, despite these known risks and enthusiastic antismoking campaigns, 12% of the U.S. women still smoke during pregnancy, resulting in the birth of 450,000 smoke-exposed infants in 2002. Due to the lack of molecular understanding of how smoking during pregnancy affects fetal growth, development, and function, it is not surprising that there is no effective intervention to prevent the damaging effects of smoke exposure on the developing fetus.

The mechanisms underlying the general effects of exposure to maternal smoking on fetal growth and viability are generally thought to be due to impaired oxygen supply to the fetus, however, the mechanisms underlying the harmful effects of smoking on lung are more much more complex. We are very much interested in unraveling the mechanisms of the chronic lung diseases in general, and due to nicotine, in particular. Understanding how this disease process is caused is the key to its effective prevention and treatment. Using state-of-the-art technology and innovative studies, our recent work has provided novel insights into the mechanism(s) of lung damage due to nicotine exposure on the developing lung. These studies are already showing great promise in terms of our ability to not only prevent and treat lung damage following nicotine exposure, but also normalize an already damaged lung.

These results are based on our fundamental discovery that infant’s lung has crucial fat containing cells that, under the influence of factors such as nicotine, transform into a muscle like cell, which is the hallmark of the damaged lung. Once this change has occurred, a normal functioning cell, which is essential for good lung function, is converted into a cell that has the potential to result in serious lung damage, problems with the oxygenation, and it makes infants more prone to asthma. We are in the process of teasing out the complex molecular pathways that determine the cell fate these crucial cells in the lung, i.e., what makes them to behave as “Good and Beneficial” cells and what makes them “Bad and Harmful” cells. And furthermore, we have already made unprecedented progress by showing that with appropriate manipulations we can make “Bad and Harmful” cells behave as “Good and Beneficial” cells. Based on this evidence, the work we have proposed can turn out to be pivotal in tackling the menace of damage due to nicotine exposure not only on the developing lung, but also in all other organ systems. This has an enormous potential of opening up novel interventional strategies to tackle a wide spectrum of nicotine-induced chronic diseases.

Hyperoxia-induced neonatal lung injury involves activation of TGF-B and Wnt signaling: Protection by rosiglitazone
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Dasgupta, C; Wang, Y; Sakurai, R; Torday, J Rehan, V ART
Yr: 2009 Vol: 296 Nbr: 6 Abs: Pg: L1031-1041

Peroxisome proliferator-activated receptor (PPAR) y agonist enhance lung maturaation in a neonatal rat model.
Periodical: Pediatric Research Index Medicus:
Authors: Wang, Y; Sakurai, R; Cerny, L; Torday, J Rehan, V ART
Yr: 2009 Vol: 65 Nbr: 2 Abs: Pg: 150-155

Mechanism of nicotine-induced up-regulation of wingless/int (Wnt) signaling in human alveolar interstitial fibroblasts.
Periodical: Experimental Lung Research Index Medicus:
Authors: Sakurai, R; Wang, Y' Cerny, L Guo, P; Torda, J; Rehan, V ART
Yr: 2009 Vol: Nbr: Abs: Pg:

Intrauterine growth restriction alters fetal lung programming by affecting essential epithelial-mesenchymal signalign pathways.
Periodical: Pediatric Pulmonology Index Medicus:
Authors: Karadag,A; Sakurai, R; Wang, Y; Desai, M ross, M; Torday, J Rehan, V ART
Yr: 2009 Vol: 44 Nbr: 7 Abs: Pg: 635-644

1alpha,25(OH)2D3 and its 3-Epimer Promote Rat Lung Alveolar Epithelial-Mesenchymal Interacations and Inhibit Lipofibroblast Apoptosis.
Periodical: American Journal of Physiology. Lung Cell Molecular Physiology. Index Medicus:
Authors: Sakurai, R; Shin, E; Fonseca, S; ; Sakurai, T.; Litonjua, A.;Weiss, S; Torday, J; Rehan, V ART
Yr: 2009 Vol: Nbr: Abs: Pg:

The effects of smoking on the developing lung: Insights from a biiologic medel for lung development, homeostasis and repair.
Periodical: Lung Index Medicus:
Authors: Rehan, V; Asotra, K, Torday, J ART
Yr: 2009 Vol: Nbr: Abs: Pg:

Physiologic vitamin S hormone 1a,25(OH)2D3 has spatial and temporal-specific actions during perinatal pulmonary maturation.
Periodical: Journal of Investigative Medicine Index Medicus:
Authors: Fonseca, S; Sakurai, R; Shin,E; Torday, J; Rehan, V ART
Yr: 2009 Vol: 57 Nbr: 01 Abs: Pg: A19, A112

Mechanism of reduced lulng injury by high frequency nasal ventilaation in a preterm lamb model of bronchopulmonary dysplasia.
Periodical: Journal of Investigative Medicine Index Medicus:
Authors: Fong, J; Lee, R; Sakaurai, R; Lane, R; Albertine, K; Torday, J; Rehan, V ABS
Yr: 2009 Vol: 57 Nbr: 01 Abs: Pg: A10

Antenatal administration of peroxisome proliferator-activated receptor (PPAR) y agonist resiglitazone (RGZ) prevents hyperoxia-induced lung injury postnatally.
Periodical: Journal of Investigative Medicine Index Medicus:
Authors: Sakurai, R; Shin, E; Corral, J; Torday, J; Rehan,V ABS
Yr: 2009 Vol: 57 Nbr: 01 Abs: Pg: A428