This proposal outlines a research training plan and project for the applicant, a predoctoral candidate with a commitment to an academic research career whose goal is to become an independent investigator in the field of developmental lung biology. Under the mentorship of an established investigator and a multidisciplinary dissertation committee, the candidate will pursue a program of education (coursework, conferences, seminars) and a research project addressing the cellular and molecular mechanisms of neonatal hyperoxia-mediated inhibited alveolar development (IAD) and abnormal vascular development (AVD), characteristic of the important clinical problem of bronchopulmonary dysplasia (BPD) in preterm infants. Hyperoxia is a predisposing factor for BPD, which is associated with low plasma and tissue concentrations of retinol (vitamin A;VA). Hyperoxia decreases vascular endothelial growth factor (VEGF), a key angiogenesis regulator, and increases activation of transforming growth factor-beta (TGF-Beta), a key profibrogenic factor. TGF-Beta activation is regulated by Thy-1, a cell surface glycoprotein. Our preliminary data indicate that hyperoxia-exposed newborn mice have decreased lung VA stores and impaired lung development and function, which are attenuated by retinoids. Our laboratory has made the novel observations that Thy-1 null mice have IAD and increased TGF-Beta activation and abnormal lung function, demonstrating that absence of Thy-1 in the developing lung leads to a lung phenotype similar to BPD. We have also shown that ?VARA?, a combination of VA and retinoic acid (RA), increases lung retinyl esters more than equimolar amounts of VA or RA alone. The objective of this project is to determine the mechanisms by which retinoids attenuate hyperoxia-induced abnormal angiogenesis and inhibited alveolarization in the developing murine lung.
Specific Aim 1 : will test the hypothesis that VARAmediated increases in VEGF attenuate hyperoxia-induced AVD.
Specific Aim 2 : will test the hypothesis that VARA-mediated decreases in TGF-Beta signaling attenuate hyperoxia-induced IAD. A vertically-integrated approach, with in vivo models (newborn mice exposed to hyperoxia or air for 2 weeks from birth) and in vitro models (neonatal murine lung endothelial cells and fibroblasts) will be used. Currently available transgenic mice (Thy-1 null), in addition to wild-type mice will be used to characterize the critical signaling pathways. Identification of mechanisms by which hyperoxia regulates VEGF and TGF-Beta in the developing lung, and how this regulation is inhibited by VARA may help development of new therapeutic strategies for BPD. Over the three years of the research training, the candidate will become proficient in bench research as well as in writing manuscripts and grants, and will refine presentation skills. She will develop other necessary skills in developing research collaborations, attend international research conferences, and will strengthen her knowledge base for an independent research career in developmental lung biology.
Bronchopulmonary dysplasia (BPD) which primarily affects premature infants is of major public health importance as effective treatment is not available, and cost of care is extremely high. BPD is characterized by abnormalities in the development of the air sacs (alveoli) and blood vessels in the lung, and exposure of developing lungs to high concentrations of oxygen leads to lung abnormalities similar to BPD. This proposal will determine the mechanisms by which vitamin A and its derivatives regulate and decrease the harmful effects of high oxygen concentrations on the developing lung.