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Rho-kinase signaling in lung development and persistent pulmonary hypertension

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I am a board certified neonatologist with an academic appointment at the University of Colorado. From early in my career I have been interested in persistent pulmonary hypertension of the newborn (PPHN) and mechanisms responsible for decreased responsiveness of some newborns with severe PPHN to inhaled nitric oxide (NO) therapy. PPHN is a clinical syndrome characterized by increased pulmonary vascular resistance (PVR), which prevents the transition from fetal to extrauterine life. Mechanisms responsible for increased PVR in severe PPHN include hypertensive vascular remodeling and impaired vascular growth. In the setting of severe PPHN, conventional therapies such as NO are usually ineffective with increased morbidity and mortality, making alternate therapies that are effective in this setting crucial. Rho-kinase is important for normal physiologic fetal functions and regulates smooth muscle cell proliferation, vascular tone and growth. Rho-kinase is activated by endothelin-1, serotonin and other potent mediators of pulmonary hypertension, and regulates NO production making rho-kinase signaling central to the pathogenesis of PPHN and an important therapeutic target. Past studies and preliminary data suggest that rho-kinase activity is essential for normal lung developmental biology and physiology, yet marked increases or sustained elevation of rho-kinase may contribute to impaired lung structure and function in the perinatal period. This paradox has not been clearly studied, and much needs to be learned regarding these mechanisms and the cellular basis for PPHN. Gaining a better understanding for the developmental regulation of rho-kinase in the normal fetus and newborn, as well as mechanisms for increased rho-kinase activity in the late gestation fetus and newborn with PPHN will lay the foundation for the development of new therapies. Our overall hypothesis is that high rho-kinase activity maintains elevated PVR in the normal fetus and further increases in rho-kinase activity during late gestation or sustained elevations in rho-kinase activity after birth contributes to the development of severe PPHN. The Perinatal Research Center (PRC) is part of the Department of Pediatrics, and is a leading center for research in fetal physiology. The PRC has developed a consistent group of senior faculty who are recognized as national and international leaders in the fields of developmental biology and fetal physiology. Using the resources at the PRC and under the guidance of my primary mentor Dr Steven Abman, I will utilize whole animal physiologic and cellular studies to better understand the developmental regulation of rho-kinase and mechanisms for rho-kinase activation during normal lung development and in PPHN. In the immediate short term this award will provide the opportunity for me to continue to study endothelial (PAEC) and smooth muscle cell (PASMC) biology in the context of lung vascular development and the pathobiology of severe PPHN. Over the study period I will develop greater expertise in fetal cardiorespiratory physiology and will also collaborate with Dr Troy Stevens and Ivan McMurtry at University of South Alabama, which will provide a unique opportunity to gain extensive expertise in cell biology and molecular methods that can help me study cellular signaling in PPHN. This collaboration will also allow me to develop skills in the isolation and characterization of microvascular endothelial cells (MVEC). MVEC regulate vascular growth in vivo, so isolation and characterization of these cells is essential and will provide the basis for future experiments and grant proposals aimed at studying the role rho-kinase plays in regulating MVEC function. The strength of this proposal is the assembly of several successful scientists who will assure both progress and success in my research career and guide me towards independence as a physician scientist.
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