A Molecular Approach to Prevent Pulmonary Dysfunction in the Intrauterine Growth

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DESCRIPTION (provided by applicant): Intrauterine growth restriction (IUGR) alters lung development, increasing the risk of respiratory compromise throughout postnatal life. Vertical integration of the cell-molecular mechanism(s) underlying this respiratory compromise offers a powerful functional genomic approach to understand the pathogenesis of chronic lung disease in the IUGR offspring. Since lung development is determined by spatio-temporally specific alveolar epithelial-mesenchymal interactions, we hypothesize that IUGR alters the key alveolar epithelial-mesenchymal signaling pathways that are essential for normal lung development. We propose utilizing a well established rodent model of 50% maternal food restriction (MFR) from day 10 of gestation to term and through postnatal day 21. This model has previously been shown to demonstrate adult-onset obesity, diabetes, and hypertension in the MFR offspring. Now our preliminary data provide clear evidence for failed alveolarization and pulmonary dysfunction in the MFR offspring. Using this model and well established molecular techniques such as lung morphometry, Real-Time-PCR, Western analysis, immunohistochemistry, laser capture microdissection, anti-sense and overexpression studies, and in vivo pulmonary function testing, we will 1) determine the effect of MFR on lung structure and function in the offspring at postnatal days 1 and 21, and months 3 and 9; 2) specifically examine how MFR affects alveolar Parathyroid Hormone-related Protein/Peroxisome Proliferator-Activated Receptor 3 signaling that is known to be essential for normal lung development; and 3) evaluate if alterations in key alveolar epithelial-mesenchymal signaling pathways affected by MFR, and the subsequent lung structural and functional changes, can be normalized by either over-expression or silencing of the key regulatory genes involved. Based on our preliminary data, we expect that, in the lung of the MFR offspring, we will find disruption in molecular pathways that are essential for alveolarization, accounting for the altered lung programming seen in the offspring, hence offering the possibility of prevention and/or reversal of such changes with specific molecular interventions. By exploiting the functional genomic approach, the studies proposed herein will translate into novel and innovative molecular preventive and therapeutic approaches for pulmonary dysfunction seen in IUGR offspring secondary to not only MFR, but also to other causes. PUBLIC HEALTH RELEVANCE: There is accumulating evidence to show that infants who are delivered following growth restriction during the fetal period have significant lung morbidity during their postnatal life. Further, since the mechanism of this lung morbidity is not known, there is no specific intervention to prevent it. Using a well established rat model of intrauterine growth restriction and the state-of-the-art technology, we propose studies that will unravel the fundamental molecular mechanism (s) of pulmonary dysfunction in the growth restricted offspring, allowing us to design novel intervention strategies that may not only prevent, but also reverse intrauterine growth restriction associated lung damage during postnatal life.