The candidate for this mentored clinical scientist development award has a strong clinical interest in pulmonary hypertension and is committed to a research career in this field, The candidate's institution has a long history of training successful clinical and basic scientists in pulmonary disorders and provides an extremely rich environment for academic career development. The sponsor is an internationally acclaimed expert in pulmonary vascular biology and has a long track record of successfully mentoring junior investigators. The Advisory Committee has experts both in eicosanoid research and hypoxic models of pulmonary hypertension. The candidate will receive closely supervised research training and a carefully selected program of didactic instruction. The research plan will test the hypothesis that leucocyte-12- lipoxygenase (L-12-LO) is a key regulator of pulmonary artery smooth muscle hyperplasia in hypoxia- induced pulmonary hypertension. Structural remodeling with proliferation of pulmonary artery smooth muscle cells (PASMCs) is a key feature of pulmonary hypertension. Recently, recruitment of mediators of inflammation has been implicated in the remodeling process. The candidate has obtained preliminary data demonstrating that: 1) the inflammatory molecule L-12-LO is significantly up-regulated in lungs of rats with hypoxia-induced pulmonary hypertension, and 2) the product of L-12-LO, 12-(S)-hydroxyeicosatetraenoic acid [12(S)-HETE] has pro-proliferative effects on PASMCs and may participate in the remodeling process.
Specific aim #1 will determine the mechanism by which hypoxia upregulates L-12-LO, specifically, it will test the hypothesis that hypoxia inducible factor HIF-1a is responsible for the activation of the L-12-LO during hypoxia.
Specific aim #2 will explore the intermediary pathways activated by 12(S)-HETE in PASMCs.
Specific aim #3 will study the participation of L-12-LO in hypoxia-induced PASMC proliferation, both in vitro and in an animal model of hypoxia-induced pulmonary hypertension. The long-term objectives of this research are to: 1) to develop expertise in the field of smooth muscle cell and molecular biology;2) to apply these skills and study the pathogenesis of hypoxia-induced pulmonary hypertension;and, based on results from this research, 3) to perform translational studies in humans with pulmonary hypertension that will lead to novel therapies for this life-threatening disorder. This award will allow the candidate to develop into a well-trained independent researcher in the field of pulmonary hypertension.
|Sagliani, Kristen D; Dolnikowski, Gregory G; Hill, Nicholas S et al. (2013) Differences between basal lung levels of select eicosanoids in rat and mouse. Pulm Circ 3:82-8|
|Preston, Ioana R; Sagliani, Kristen D; Warburton, Rod R et al. (2013) Mineralocorticoid receptor antagonism attenuates experimental pulmonary hypertension. Am J Physiol Lung Cell Mol Physiol 304:L678-88|
|Yarovinsky, Timur O; Mohning, Michael P; Bradford, Mary A et al. (2005) Increased sensitivity to staphylococcal enterotoxin B following adenoviral infection. Infect Immun 73:3375-84|