This is a proposal for a mentored training program designed to develop an academic career in translational cardiopulmonary research. The candidate has successfully completed a clinical and research fellowship in Pediatric Critical Care Medicine at the University of California, San Francisco (UCSF), and is now prepared to fully develop and refine skills necessary to sustain an independent research program, utilizing the renowned, multidisciplinary environment offered by the Cardiovascular Research Institute (CVRI) at UCSF. The candidate will utilize an integrated approach to address mechanisms of lung fluid homeostasis associated with congenital heart defects and increased pulmonary blood flow (PBF). The mentor, Jeffrey R. Fineman, M.D., is Professor of Pediatrics and Investigator in the CVRI at UCSF. He is an internationally recognized expert on pulmonary vascular disease, and has an extremely strong history of successful mentorship. In addition, an advisory committee of distinguished biomedical investigators will provide critical scientific review on key aspects of this proposal: Drs. Michael Matthay, Donald McDonald, and Dallas Hyde are world-renowned for their expertise in the field of lung water and lung injury, lung lymphatics, and stereology and lung structure, respectively. The research plan seeks to elucidate the mechanisms underlying lung fluid homeostasis in the context of increased PBF that is associated with common congenital heart defects. Utilizing a unique, clinically relevant ovine model of a congenital heart defect with increased PBF (created in utero by a surgically-placed aortopulmonary graft), we have generated in vivo data indicating that chronically increased PBF is associated with (1) impaired relative lymphatic flow, (2) decreased bioavailable nitric oxide, (3) delayed transit kinetics through the pulmonary lymphatics, (4) aberrations in lymphatic architecture, and (5) alterations in the expression of proteins associated with lymphatic growth, such as vascular endothelial growth factor-c. Based on these findings, our overall hypothesis is that chronically increased PBF leads to impaired pulmonary lymphatic endothelial function, resulting in perturbation in lymphatic flow and postnatal development. By integrating whole animal, organ-based, molecular, isolated vessel, cell-culture, and biochemical experiments, this proposal seeks to accomplish the following: to characterize the effects of chronic increases in PBF on lung fluid balance, and to elucidate the mechanisms controlling these changes. In particular, the signaling pathways that regulate pulmonary lymphatic vascular function and post-natal lymphatic growth and remodeling will be examined.
For infants and children afflicted with congenital heart defects that lead to increased blood flow to the lungs, significant morbidity and mortality can be attributed to increased lung water, impairment of normal respiratory function, and an increased metabolic burden on an overtaxed cardiovascular system. Current medical therapy for these patients is primarily limited to diuretic medications, aimed at alleviating respiratory symptoms until corrective or palliative surgery is performed. Unfortunately, this nonspecific therapy can result in untoward effects, such as electrolyte abnormalities and dehydration that are particularly harmful in pediatric cardiac patients. The lack of therapeutic strategies for these children is in part due to a fundamental gap in our understanding of the mechanisms that regulate lung fluid balance in this setting. We believe that the lung's lymphatic vasculature plays a crucial role in maintaining lung fluid balance, and this is the focus of our current investigations. By understanding the mechanisms that regulate lymphatic function, we hope to develop new clinical strategies and interventions to more effectively manage these vulnerable patients.