Research
The following research efforts are underway in the Division of Neonatology at Cincinnati Children's Hospital Medical Center:
Interest in host defense proteins in the lungs. Current focus is on lysozyme, an enzyme that cleaves peptidoglycan in the cell wall of bacteria. Lysozyme is ubiquitously distributed and is especially abundant in the lungs. Activity is investigating the role of lysozyme in vivo with mouse models in which levels of lysozyme protein in lungs are increased 6-fold and lysozyme enzyme activity in lung fluid is increased 16-fold. Mice that are deficient in lysozyme are also challenged with clinically relevant pathogens to assess the role of lysozyme in vivo.
Directs a laboratory studying the genetics of heart development in zebrafish. His work focuses on identifying the genetic pathways which control endocardial cushion and heart valve development, since errors in these morphogenetic steps accounts for the majority of congenital heart malformations in neonates. His work also seeks to identify the mechanism by which heart function during very early embryogenesis affects later steps of heart formation--this work rising from his discovery that zebrafish hearts with poor myocardial function cannot complete endocardial cushion formation. [Visit the Bartman Lab.]
Principal investigator for the Cincinnati component of the 16-site NICHD Neonatal Research Network including ongoing clinical trials: a factorial design, randomized trial of early CPAP and/or lower oxygen saturations to reduce the risk of BPD and ROP and a randomized trial of the effect of early versus late phototherapy on neurodevelopmental outcome; and a randomized trial of supplemental oxygen to prevent progression of retinopathy of prematurity. Dr. Donovan is also principal investigator of a study, funded by the Gerber Foundation, to develop a model for prediction of NEC risk to be used to identify infants for trials of preventative therapies.
Principal investigator of the Vermont Oxford Neonatal Network Database.
- Principal Investigator for the Cincinnati site (Neonatal Network Study)
- Inhaled Nitric Oxide for Preterm Infants with Severe Respiratory Failure
Principal Investigator for the Cincinnati site (Neonatal Network Study) Neurodiagnostic Evaluation that Assist in the Prediction of Adverse Outcome Following Acute Perinatal Asyphyxia Principal Investigator for the Cincinnati site (Neonatal Network Study) Association of Apolipoprotein E (apoE) Genotype with Brain Injury and Neurodevelopmental Outcome in Infants with Hypoxic Ischemic Encephalopathy Principal Investigator at the Cincinnati Children's Hospital Medical Center for The Congenital Diaphragmatic Hernia Study Group Database. Principal Investigator at the Cincinnati Children's Hospital Medical Center for The Vermont-Oxford Network. Research in our laboratory focuses on developmental biology of pulmonary vascular development. Recent investigations have examined how vascular endothelial growth factor (VEGF) mediates pulmonary vascular, lymphatic and airway development as well as alveolarization. Using in vitro cell lines as well as mouse models incorporating inducible transgenes, we are studying how VEGF mediates organization of pulmonary vasculature during late fetal life. We also identified potential pathologic pulmonary conditions mediated by inappropriate VEGF expression. An additional path of investigation is directed toward understanding how certain proteins implicated in axonal guidance during central nervous system development, also direct developmental processes in the lung. [Visit The Akeson Lab.]
Recognized expert on fetal and neonatal skin development. His particular research interests focus on the biology of vernix caseosa and the role of the skin in innate immune function and sensory transduction. As a practicing neonatologist, he is particularly interested in skin-based sensing systems for noninvasive biomedical monitoring and measurement. He is the editor of the book Neonatal Skin: Structure and Function (2003). He is co-chair of the 2005 Gordon Research Conference on Barrier Function of Mammalian Skin. Dr. Hoath was one of 8 international investigators participating in the first joint effort by NASA and the National Institutes of Health to study the effect of spaceflight and zero gravity on mammalian pregnancy and fetal development.
Alan Jobe has been continuously funded by NIH, since 1977, for a series of research studies focusing on surfactant, lung development and lung injury. His present research interests are to better understand the pathophysiology and treatment of bronchopulmonary dysplasia. He uses fetal sheet models of chorioamnionitis and chronic infection to explore how the fetus responds to inflammation and how that may contribute to BPD. A new direction of that research is to evaluate innate immune modulation in the fetus and its effect on postnatal immune function. Other studies are to characterize how the components of neonatal resuscitation (ventilation variables, oxygen) injure the preterm lung and how that initial injury may progress to BPD.
My laboratory is interested in how antenatal inflammation -- one of the most common causes of premature delivery -- causes lung injury, modulates lung development and is an antecedent to bronchopulmonary dysplasia (BPD). My laboratory works closely with Drs. Alan Jobe, Cindy Bachurski, Machiko Ikegami in Cincinnati and our collaborators in Western Australia. Our animal model is preterm lambs exposed to intra-amniotic (IA) injection of pro-inflammatory agents such as E. Coli endotoxin or recombinant IL-1. We find that in this model endotoxin causes inflammation in chorio-amnion and lung. We have recently developed a preterm sheep model of ureaplasma chorio-amnionitis mimicking the human disease.
Our present efforts are directed in understanding the molecular mechanisms and pathways involved in lung maturation and lung injury, particularly vascular injury in the lung in this model. We employ a variety of molecular biology techniques such as cloning new genes, making libraries, express recombinant protein and others in our research work. Recently, we have made some novel and interesting observations regarding endotoxin tolerance, in both systemic granulocytes and as well as the lung in preterm sheep. Thus, study of innate immunity as relevant to the pathogenesis of BPD is also an area of increasing interest in the laboratory. The animal work and physiology is done in Western Australia and the molecular, biochemical and cell biology work is done in Cincinnati.
Major research efforts are to determine pathophysiologic alterations contributing to the development of lung inflammation in children, particularly alterations contributing to chronic lung disease. Studies are to determine mechanisms where the innate immune system or downstream signaling pathways control lung inflammation or alter development of the neonatal lung. SP-A and D are members of the collectin family of the innate immune system expressed at high levels by the lung epithelium. Current research is to determine the roles of SP-A and SP-D in protection of the developing and mature lung from inflammatory injury using cell culture and mouse models of SP-A or D deficiency or over production. Additional research is to determine the role played by signaling through the epidermal growth factor receptor in modulating postnatal lung development or protection of the lung from injury.
While improvements in neonatal care result in more infants surviving premature birth, nearly half of these premature infants (born at ~ 26 weeks gestation) go on to develop bronchopulmonary dysplasia (BPD). BPD, also known as chronic lung disease of early infancy, is a major cause of death and disability in premature infants. As a result, BPD still represents a major public health problem. In the premature infant, BPD is believed to be due to injury to and disruption of the infant's immature and still actively developing lungs. The regulation of normal alveolar and vascular development in the newborn lung is poorly understood. The Le Cras Laboratory focuses its work on the role of growth factors in postnatal lung development and the pathogenesis of BPD. For further information and publications, please visit the Le Cras lab web site.
Worked with Cincinnati Children's administration and the Deloitte Touche Consulting Group to create a global plan for chronic care. He also worked on projects for special needs patients, including daycare for the chronically ill, an expanded family resource center, and recycling of used equipment to patients in need. Dr. Levin completed a software program to be utilized as a charting and database for Level I and II newborn nurseries.
Type II cells serve many important function in the lung, including the role of progenitor cell for the alveolar lining. The Rice laboratory utilizes the isolated murine Type II cell model to define growth factors regulating Type II cell proliferation and differentiation. A better understanding of Type II cell growth may provide new approaches to therapy for a wide range of lung disorders. Type II cells also produce surfactant and we are examining the processing of surfactant protein C since aberrant processing of surfactant protein C is known to cause interstitial lung disease.
Co-director of the Clinical Research Steering Committee and will assume to role of principal investigator of the NICHD Neonatal Network at CCHMC with the competing renewal in 2006. He is a participant in the Necrotizing Enterocolitis (NEC) Working Group whose aims are to develop novel strategies for prevention and treatment of NEC. The following studies exemplify work being conducted by this interdisciplinary group.
- "Development of a statistical model that could predict the risk for NEC", Edward Donovan, MD, Barb Warner, MD, Jareen Meinzen-Derr, MPH., and Kurt Schibler, MD
- "Epidermal Growth Factor for the Prevention of Necrotizing Enterocolitis in Premature Infants" Barbara Warner MD, Brad Warner MD and Christopher Erwin PhD
- "Interleukin-11 Administration For The Prevention Of Necrotizing Enterocolitis In Very Low Birth weight Infants" Kurt Schibler, MD.
Also, Dr. Schibler has been involved with thematic collaborative efforts with the Center for Epidemiology and Biostatistics in areas of innate mucosal immunity and delineating the role of human milk in infant health. One example of these endeavors is a study entitled "Correlation of Histo-Blood Group Genotype with Candida Infections among VLBW Infants". This is a secondary study to the NICHD Anonymized Database Linked to Anonymized Blood Sample of Studies of Genomic Impact on Morbidity and Mortality Among High-Risk Infants.
Dr. Schibler is involved in other efforts to incorporate genomic research into NICHD Neonatal Research Network trials. Examples of two such endeavors are:
- "DNA Repository for SUPPORT" Michael Cotten MD and Kurt Schibler, MD. A secondary study to NICHD Neonatal Network Study, Surfactant, Positive Airway Pressure, Pulse Oximetry, Randomized Trial and Oxygenation (SUPPORT): A Factorial Randomized Control Trial in Extremely Low Birth Weight Infants.
- "Mitochondrial Mutation Screening in At-Risk Neonates". John Greinwald MD, Louise Lawson PhD, Valentina Pilipenko PhD, Jareen Meinzen-Derr MPH, Daniel Choo MD. Dr. Schibler facilitated submission of this secondary study to the NICHD Anonymized Database Linked to Anonymized Blood Sample of Studies of Genomic Impact on Morbidity and Mortality Among High-Risk Infants.
Interested in Very Low Birth Weight (VLBW) population, with a focus on the prediction and prevention of Necrotizing Enterocolitis (NEC). Currently involved in clinical trials on the prevention of NEC with Epidermal Growth Factor. Additional interests include the prediction of NEC based on risk factor modeling and prevention with use of human milk. Secondary interest is in the role of perinatal regionalization and hospital delivery systems in improving VLBW outcomes.
The Whitsett Laboratory is a well-established laboratory that has focused its attention to the elucidation of genetic pathways regulating lung function and formation. The roles of surfactant proteins in lung function have been an active area of study. Mechanisms controlling lung-specific gene transcription, including the roles in mechanisms and targets a number of critical factors include NKX2.1, Fox, Sox, GATA, NFAT, ets-family members and other genes which are studied in vivo and in vitro. Genetic pathways mediating paracrine interactions critical for lung morphogenesis including ß-catenin, FGF, sonic hedgehog are being studied. Roles of transcription factors in establishing stem cell niches and progenitor cells critical for lung formation and repair are being elucidated. The laboratory makes extensive use of conditional gene targeting in addition and bioinformatics in the study of lung morphogenesis and function. Genes affecting postnatal lung homeostasis including the surfactant proteins, CFTR and genes causing acute and chronic lung disease have been identified. The mechanisms by which they contribute to lung diseases are being sought. There are opportunities for study of established and novel pathways critical for lung formation and function within the laboratory.
