Over the past 20 years, the Cornfield Laboratory has focused upon basic, translational and clinical research, with a primary focus on lung biology. As an active clinician-scientist, delivering care to acutely and chronically ill infants and children, I have noted the evolution of chronic and acute lung diseases in infants and children in terms of disease manifestation, diagnosis, management and epidemiology. Accordingly, the areas of emphasis of the laboratory continue to evolve, shift, and even occasionally change entirely. Currently, the Laboratory is engaged in 4 distinct, but related areas of research.
Areas of Research
Early contributions were focused upon the regulation of perinatal pulmonary vascular tone. Our Laboratory addressed the subcellular mechanisms that underlie the postnatal adaption of the pulmonary circulation. Key publications demonstrated that pulmonary artery endothelial cells produced endothelial-derived relaxing factor (EDRF), subsequently identified as nitric oxide (NO), in response to ventilation, oxygenation and shear stress. Further work demonstrated that oxygen, one of the key stimuli for perinatal pulmonary vasodilation, as well as NO acts via quantal and localized release of calcium from ryanodine-sensitive stores to prompt activation of the pulmonary artery smooth muscle cell calcium-sensitive potassium channels. These papers informed the development of several clinical trials wherein the efficacy of inhaled nitric oxide in persistent pulmonary hypertension of the newborn was established.
With improved obstetrical and neonatal care, more, smaller and less developmentally mature infants are surviving even extreme prematurity. Our Laboratory is interested in two fundamental questions surrounding chronic lung disease of infancy. First, whether and how might exposure of oxygen levels in excess of the normally low intrauterine oxygen tension state of the intrauterine environment might compromise lung development. Second, as pulmonary hypertension complicates chronic lung disease of infancy in ~30% of cases, our Laboratory is focusing on the molecular mechanisms that underlie the increase in pulmonary artery blood pressure and identification of novel therapeutic tools to control blood pressure and promote lung development.
Over the past several years, our lab has been engaged in experiments that address the regulation of pulmonary vascular tone. We have investigated the signal transduction pathway of molecules that play an important role in determining pulmonary vascular tone. Relatively recently, we identified a novel, and controversial, role for HIF-1a in the regulation of tone in lung via effects on myosin light chain phosphorylation in the pulmonary artery smooth muscle cells and in regulating expression of the b1 subunit of the calcium sensitive potassium channel. Further, we outlined a novel role for endothelin derived from PASMC in modulating the pulmonary vascular response to hypoxia. Most recently, we have undertaken a line of research using human tissue to ensure fidelity between findings in mouse models and human biology.
In considering how best to mitigate neonatal morbidity and mortality, we embarked on an exploratory line of research in preterm labor wherein our expertise in vascular biology, smooth muscle and ion channel physiology might be leveraged to address abnormal uterine contractility. Thus, over the past 5 years, we have became increasingly focused upon uterine contractility. Important discoveries in this area include identification an ion channel, transient receptor potential vanilloid 4, that plays a central and critical role in the control of uterine tone during both quiescence and activation. Our laboratory has created multiple experimental models, established collaborations, and acquired reagents (specifically genetically modified mice) that allow us to rigorously and mechanistically probe the cellular and molecular underpinnings of both physiologic and pathophysiologic labor. We are poised to build upon our recent findings with a team of scientists and clinicians to create new knowledge and consider how best to move the discoveries from bench to bedside.
Among the most difficult clinical issues to manage is acute respiratory distress syndrome (ARDS). Mortality rates are high as well as considerable morbidity. For reasons that remain incompletely understood, children with ARDS are more likely to survive than adults with similar severity of illness. Our laboratory has been interested in the reasons that underlie the seemingly more well-preserved barrier function in children compared to adults. Using cell lines and a murine model of lung injury, we have identified that the expression of focal adhesion kinase, a molecule responsible for maintaining barrier function increases in expression increases more rapidly in response to either an inflammatory stimulus or hypoxia.
The goals of single cell RNAseq project are to define the heterogeneity of murine pulmonary cell types, their distinct subpopulations and dynamic changes in gene expression, and to understand the adaptive genetic switches throughout lung development.