Genetic Investigation of pulmonary lymphatic development and function

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DESCRIPTION (provided by applicant): Respiratory distress syndrome (RDS) associated with immature lung development affects over 16,000 premature infants annually in the US. The pathogenesis of RDS is attributed primarily to the lack of surfactant, a protein-lipid complex required to improve lung compliance and enable newborn infants to inflate their lungs and breath. Lymphatic vessels appear in the lung in mid- gestation and have been proposed to play roles in draining the lung of fluid in preparation for birth and neonatal respiration. However, studies to define the role of pulmonary lymphatic vessels utilizing catheter-based and surgical approaches developed for blood vessel investigation have not revealed any critical roles in neonatal respiration. Our preliminary studies using genetically modified mice that lack lymphatic function refute these conclusions, and reveal that mice lacking lymphatic vessels die at birth due to lack of lung inflation and neonatal respiratory failure. Our studies of mice lacking the lymphangiogenic factor CCBE1 or signaling by the VEGFR3 receptor do not reveal any molecular or cellular abnormalities in lung development. Instead, we find that loss of lymphatic function is associated with reduced prenatal lung compliance despite preserved surfactant production. The goal of this proposal is to fully define how lymphatic's develop in the mammalian lung and what their prenatal and neonatal functions in that organ are. In Aim 1 we will study the molecular and cellular processes of lymphatic vascular development using newly generated lines of mice in which lymphangiogenic factor expression can be followed by reporter genes and altered through conditional gene deletion. In Aim 2 we will define a new mechanical role of lymphatic function in regulating the compliance of the developing and neonatal lung. We expect these studies to define a new role for lymphatic's in neonatal respiration, and to stimulate the development of new lymphatic-based strategies to treat RDS in premature infants.