Christiane Dammann, MD
The main research interest of my laboratory is to discover new therapies to prevent the development of long-term respiratory disability and disease in preterm infants. We are studying lung cell differentiation in normal lung development and neonatal lung injury in order to determine new therapeutic approaches to advance lung development and prevent injury in the setting of preterm birth. We are specifically interested in elucidating endogenous lung development promoting factors such as the interaction between Neuregulin, ErbB4, and TTF-1 in differentiating fetal lung type II epithelial cells.
Our overall goal is to manipulate endogenous processes to promote cell differentiation prenatally and prevent postnatal injury-induced lung cell remodeling. In the clinical NICU setting, I am leading clinical therapeutic trials to minimize lung disease. I have received formal training as a pediatrician and neonatologist, and completed research fellowships in developmental and cancer biology at Tufts and Harvard University. I am the Director of the Developmental Biology Basic Science Laboratory and the Perinatal Neonatal Fellowship Training Program in the Division of Newborn Medicine at the Floating Hospital for Children at Tufts Medical Center. I also hold a faculty appointment at the Cell Molecular and Developmental Biology Program at the Sackler School for Graduate Biomedical Sciences at Tufts University.
The following publications are some examples of our work:
Purevdorj E, Zscheppang K, Hoymann HG, Braun A, von Mayersbach D, Brinkhaus M, Schmiedl A, Dammann CEL. ErbB4 deletion leads to changes in lung function and structure similar to bronchopulmonary dysplasia. Am J Physiol Lung Cell Mol Physiol 2008 Mar;294(3):L516-22. http://www.ncbi.nlm.nih.gov/pubmed/18203811
Hoffmann I, Bueter W, Zscheppang K, Brinkhaus MJ, Liese A, Riemke S, Dörk T, Dammann O, Dammann CE. Neuregulin-1, the fetal endothelium, and brain damage in preterm newborns.
Brain Behav Immun. 2010 Jul;24(5):784-91. doi: 10.1016/j.bbi.2009.08.012.http://www.ncbi.nlm.nih.gov/pubmed/19733651
Liu W, Purevdorj E, Zscheppang E, von Mayersbach D, Brinkhaus M-J, Schmiedl A, Dammann CEL. Fetal ErbB4 deletion delays functional and structural lung development. Biochim Biophys Acta 2010 Jul;1803(7):832-9. http://www.ncbi.nlm.nih.gov/pubmed/20303366
Hoeing K, Zscheppang K, Mujahid S, Murray S, Volpe MA, Dammann CE, Nielsen HC. Presenilin-1 Processing of ErbB4 in Fetal Type II Cells is Necessary for Control of Fetal Lung Maturation. Biochim Biophys Acta. 2011 Mar;1813(3):480-91, PMC3046222. http://www.ncbi.nlm.nih.gov/pubmed/21195117
Zscheppang K, Dörk T, Schmiedl A, Jones A, Dammann CEL. ErbB4 regulates fetal surfactant protein B expression at the transcriptional level. Am J Respir Cell Mol Biol. 2011 Oct;45(4):761-7. http://www.ncbi.nlm.nih.gov/pubmed/21317380
Zscheppang K, Konrad M, Zischka M, Huhn V, Dammann CEL. Estrogen-Induced Upregulation of Sftpb Requires Transcriptional Control of Neuregulin Receptor ErbB4 in Mouse Lung Type II Epithelial Cells. Biochim Biophys Acta. 2011 Oct;1813(10):1717-27. http://www.ncbi.nlm.nih.gov/pubmed/21777626
Schmiedl A, Behrens J, Zscheppang K, Purevdorj E, v. Mayersbach D, Liese A, Dammann CEL. Lipopolysaccharide-Induced Injury is more pronounced in the developing lungs of fetal transgenic ErbB4 deleted mice. Am J Physiol Lung Cell Mol Physiol. 2011 Oct;301(4):L490-9. http://www.ncbi.nlm.nih.gov/pubmed/21724861
Huang Z, Wang Y, Nayak PN, Dammann CEL, Sanchez-Esteban J. Stretch-induced fetal type II cell differentiation is mediated via ErbB1 - ErbB4 interactions. J Biol Chem. 2012 May 25;287(22):18091-102. http://www.ncbi.nlm.nih.gov/pubmed/22493501
Knoll AB, Brockmeyer T, Chevalier R, Zscheppang K, Nielsen HC, Dammann CE. Adult rat bone marrow-derived stem cells promote late fetal type II cell differentiation in a co-culture mode. 2013. The Open Respiratory Medicine Journal 2013; 7:33-40. http://www.ncbi.nlm.nih.gov/pubmed/23730368
Zscheppang K, Giese U, Hoenzke S, Wiegel D, Dammann CEL. ErbB4 is an Upstream Regulator of TTF-1. Biochim Biophys Acta 2013, in press. http://www.ncbi.nlm.nih.gov/pubmed/23845988
Olaf Dammann, DrMed, SM
Director of Clinical Research
My research is in the field of perinatal neuroepidemiology. The major goal is to identify and characterize risk factors for brain damage in newborns. One focus of this work is on intrauterine infection and the fetal inflammatory response.
Dammann O, Leviton A. Perinatal brain damage causation. Dev Neurosci 2007;29:280-8
Wolfberg AJ, Dammann O, Gressens P. Anti-inflammatory and immunomodulatory strategies to protect the perinatal brain. Semin Fetal Neonatal Med 2007;12:296-302
Dammann O. Persistent neuro-inflammation in cerebral palsy: a therapeutic window of opportunity? Acta Paediatr 2007;96:6-7.
Dammann O, Bueter W, Leviton A, Gressens P, Dammann CE. Neuregulin-1: A Potential Endogenous Protector in Perinatal Brain White Matter Damage. Neonatology 2007;93:182-7.
Dammann O, Leviton A. Maternal intrauterine infection, cytokines, and brain damage in the preterm newborn. Pediatr Res 1997;42:1-8.
Jonathan Davis, MD
Dr. Jonathan Davis is Vice-Chair of Pediatrics and Chief of Newborn Medicine at the Floating Hospital for Children at Tufts Medical Center and Professor of Pediatrics at Tufts University School of Medicine. His research has focused on breathing problems in newborn infants, causes of newborn brain injury, and neonatal drug development. He has authored over 150 manuscripts and book chapters and received numerous grant awards from the National Institutes of Health, the FDA, the March of Dimes, the American Lung Association and many others. Dr. Davis has lectured worldwide including the Vatican Children’s Hospital in Rome, the Pasteur Research Institute in Paris, and the National Academy of Sciences in Washington.
Dr. Davis has conducted the basic science and animal studies to support human trials of exogenous surfactant, human recombinant antioxidants, human recombinant anti-inflammatory agents (rhCC10), and many other drugs and devices in newborn infants and has been intimately involved in trial design, data collection, data analyses, and peer-reviewed publications. He is currently funded by NIH and FDA to develop: 1) better biomarkers and outcome measures for clinical trials in preterm infants and; 2) new and existing therapeutics to improve neonatal outcome. Dr. Davis played an active role in the passage of legislation to promote new product development in children (FDASIA) and was appointed Chair of the Neonatal Advisory Committee in the Office of the Commissioner at FDA. He is a member of the Operations Group of the CTSA Consortium Child Health Oversight Committee (CC-CHOC – just stepped down as Chair), the Pediatric Therapeutics Initiative of CC-CHOC, and the BPCA Prioritization Committee at NIH. These positions permit him to work closely with NIH, FDA, academic leaders, and Industry to promote the development of important pediatric therapeutics.
Lee J, Davis JM. Future applications of antioxidants in premature infants. Curr Opinion Pediatr 23:161-6, 2011
Kazzaz JA, Strayer M, Wu J, Malone DJ, Koo H, Shaffer TH, Strayer DS, Davis JM, Wolfson MR. Perfluorochemical-liquid adenovirus suspensions enhance gene delivery to the distal lung. Pulmonary Med 2011:918036, 2011
Parad RB, Davis JM, Allred E, Rosenfeld WN. The incidence and severity of retinopathy of prematurity is reduced in preterm infants receiving recombinant human superoxide dismutase. Neonatology 102:139-44, 2012
Lee JW, Silfa-Mazara F, Rivera L, Davis JM. Retinopathy of prematurity in the Dominican Republic: Challenges to screening and prevention. Am J Perinatol, 29:801-6, 2012
Davis JM, Connor EM, Wood AJ. The need for rigorous evidence on medication use in preterm infants: is it time for a neonatal rule? JAMA 308:1435-6, 2012
Wang CJ, Little AA, Kamholz K, Holliman JB, Wise M, Davis J, et al. Strategies to improve retinopathy of prematurity follow up: Exploration of family, provider, and systems issues. Arch Ophthalmol 130:1433-40, 2012
Afolayan AJ, Eis A, Teng RJ, Bakhutashvili I, Kaul S, Davis JM, Konduri GG. Alterations in manganese superoxide dismutase activity in persistent pulmonary hypertension of the newborn. Am J Physiol: Lung Cell Mol Physiol 303:L870-9, 2012.
Wachman EM, Hayes MJ, Brown MS, Paul J, Harvey-Wilkes K, Terrin N, Huggins GS, Aranda JV, Davis JM. OPRM1and COMT single nucleotide polymorphisms reduce the incidence and severity of Neonatal Abstinence Syndrome. JAMA 309:1821-7, 2013
Byington CL, Higgins S, Kaskel FJ, Purucker M, Davis JM, Smoyer WE. The Clinical and Translational Science Award KL2 Program: Supporting the careers of child health investigators. Clin Trans Sci, in press.
Heber Nielsen, MD
Professor of Pediatrics and Anatomy and Cell Biology
My focus is on the fibroblast-type II cell communication process which directs maturation of surfactant production, and how this may be disrupted by competing signals and lung injury. Epidermal growth factor (EGF) controls fibroblast communication to type II cells. Communication to the type II cell is accomplished through a second growth factor neuregulin (NRG). Both EGF and NRG are ligands of the ErbB receptor family. My work focuses on the how EGF promotes the production and intracellular processing of NRG for release to act on type II cells, and on the mechanisms regulating the expression and activation of ErbB receptors in both fetal lung fibroblasts and type II cells.
Chetty A, Manzo N, Waxman A, Nielsen HC. Modulation of insulin-like growth factor binding protein-2 and -3 in hyperoxic injury in developing rat lung. Pediatric Research 58:222-228, 2005
Chetty A, Cao GJ, Nielsen HC. Insulin-like growth factor-1 signalling mechanisms, type I collagen and alpha smooth muscle actin in human fetal lung fibroblasts. Pediatric Research 60:389-394, 2006
Dammann CEL, Nassimi N, Liu W, Nielsen HC. Dexamethasone interacts with ErbB signaling in fetal mouse lung surfactant synthesis. European Respiratory Journal 28:1117-1123, 2006
Zscheppang K, Korenbaum E, Bueter W, Ramadurai S, Nielsen HC, Dammann CEL. ErbB4 receptor dimerization, localization and co-loclization in mouse lung type II epithelial cells. Pediatric Pulmonology 41:1205-1212, 2006
Villanueva D, Wang K, Nielsen HC, Ramadurai SM. Expression specific protein kinase C isoforms and ligand-specific activation of PKCa in late gestation fetal lung. Experimental Lung Research 33:185-196, 2007
Liu W, Zscheppang K, Murray S, Nielsen HC, Dammann CEL. The ErbB4 receptor in fetal rat lung fibroblasts and type II cells. Biochimica et Biophysica Acta 1772:737-747, 2007
Zscheppang K, Liu W, Volpe MV, Nielsen HC, Dammann CEL. ErbB4 regulates fetal surfactant phospholipid synthesis in primary fetal rat type II cells. American Journal of Physiology (Lung Cellular Molecular Physiology) 293:429-435, 2007
Chetty A, Cao G-J, Manzo N, Nielsen HC, Waxman A. The role of IL-11 and IL-6 in hyperoxic injury in developing lung. Pediatric Pulmonology In Press:-, 2008
MaryAnn V. Volpe, MD
Proper morphogenesis of the fetal lung is a crucial but poorly-understood feature of fetal lung development. My research focuses on the morphoregulatory Hox proteins as master controls for specific events during airway formation and lung growth. The necessity of understanding Hox protein regulation of lung development cannot be understated as Hox proteins interact with many currently known regulators of lung development and maturation. However, these interactions have not been studied in the lung. My work has established that normal expression of Hoxb-5 is important for airway morphogenesis. Bronchopulmonary sequestration, and congenital cystic adenomatoid malformation, lung tumors which develop in the fetus, are associated with dysregulation of Hoxb-5 expression. Current work uses both in vivo and in vitro techniques, focusing on understanding how Hox protein regulation/dysregulation modulates downstream gene signaling during lung development and maturation, in lung repair, and in congenital and acquired lung disease in the newborn infant.
Volpe MV, Vosatka RJ, Nielsen HC. Hoxb-5 control of early airway formation during branching morphogenesis in the developing mouse lung. Biochim Biophys Acta 2000; 1475: 337-345.
Archavachotikul K, Ciccone TJ, Chinoy MR, Nielsen HC, Volpe MV. Thyroid hormone affects embryonic lung branching morphogenesis and cellular differentiation. Am J Phys 2002; 282: L359-369.
Chinoy MR, Nielsen HC, Volpe MV. Mesenchymal nuclear transcription factors in nitrofen-induced hypoplastic lung. J Surg Research 2003; 108:203-211.
Volpe MV, Pham L, Lessin M, Ralston SJ, Bhan I, Cutz E, Nielsen HC. Expression of Hoxb-5 during human lung development and in congenital lung malformations. Birth Defects Research Part A:Clinical and Molecular Teratology 2003; 67:550-556.
Volpe MV, Ramadurai SM, Pham LD, Nielsen HC. Hoxb-5 down regulation alters tenascin-C, FGF10, and Hoxb gene expression patterns in pseudoglandular period fetal mouse lung. Frontiers in Bioscience. 2007; 12: 860-873
1. Improving Outcomes in Neonatal Abstinence Syndrome.
Drs. Davis, Dammann, Smith; Funded by the National Institute of Drug Abuse (NIDA).
Misuse of opioids and other psychoactive drugs during pregnancy is a significant problem in the US. Neonatal abstinence syndrome (NAS) affects most infants exposed to opioids in utero
, although its expression is variable. Optimal treatment of NAS has not been established, with studies limited to short term outcomes, with longer term safety and efficacy undefined. In addition, genetic factors that may contribute to the severity of NAS have not been studied in newborns. The goals of this proposal are: 1) to demonstrate short and long term benefits of pharmacotherapy of NAS in the newborn period (leading to FDA approval) and; 2) to explore how genetic variations in narcotic metabolism and pharmacodynamics contribute to the pathogenesis of NAS. Results should significantly improve our understanding of NAS and elucidate how different therapeutic regimens can influence immediate and long term neurodevelopmental outcome.
First, 184 term infants needing treatment for NAS will be randomized to receive either morphine or methadone in a double blind, double dummy design. It is hypothesized that morphine treated infants will require significantly fewer days in the hospital compared to methadone treated infants. Next, the effects of NAS treatment on infant neurodevelopment at 18 months of age will be assessed using the Bayley III Scales of Infant Development. It is hypothesized that morphine treated infants will have better neurodevelopmental outcome at 18 months compared to methadone treated infants. Finally, single nucleotide polymorphisms (SNPs) in the multi-drug resistance (MDR1), mu opioid receptor (OPRM1), and/or catechol-O-methyltransferase
(COMT) genes (pharmacogenetic modulators of opioid action) will be analyzed and correlated with short term outcomes and neurodevelopment assessments to determine if genetic variation is important in the pathogenesis of NAS. Preliminary data does suggest that genetic variation does influence the incidence and severity of NAS. The results of these studies will enhance our understanding of the pathogenesis of NAS, define best treatment practices, promote early identification of those at highest risk for neurodevelopmental impairment, and facilitate targeted interventions to improve outcomes in these high risk infants.
2. Reducing Acute and Chronic Lung Injury in Preterm Infants with Recombinant Human Clara Cell Protein (rhCC10).
Drs. Davis, Dammann, Smith; funded by the Food and Drug Administration’s (FDA) Orphan Drug Program.
Recombinant human CC10 protein (rhCC10) is a novel therapeutic agent used to prevent the development of chronic respiratory morbidity (CRM; repeated respiratory infections, asthma, re-hospitalizations) in preterm infants. Native CC10 is a natural anti-inflammatory and immunomodulatory factor produced by Clara Cells in the lung and is the most abundant protein in respiratory mucosa. Animal data demonstrate that a single intratracheal dose of rhCC10 administered shortly after birth reduces lung inflammation (important biomarkers linked to lung injury in preterm infants), promotes normal lung development, preserves lung architecture, improves pulmonary function, suppresses the response to endotoxin, and enhances resistance to pulmonary infections. In preterm infants who die or develop lung inflammation and subsequent bronchopulmonary dysplasia (BPD), both the concentration and activity of CC10 are significantly reduced, indicating that CC10 is essential for preventing lung injury and promoting normal lung development. In a small phase I study, rhCC10 significantly decreased several indices of pulmonary inflammation in the lungs of premature infants who were at risk of developing BPD and associated CRM. The drug appeared to be safe, well-tolerated, and reduced the risk of re-hospitalization due to respiratory illness for 9-10 months after a single intratracheal dose at the time of birth (0/11rhCC10-treated infants vs. 3/6 placebo-treated). This supports the protective role of rhCC10 against damage from hyperoxia, mechanical ventilation, inflammation, and infection in the immature lung. A more normal airway epithelium will produce significantly more endogenous CC10, with both factors contributing to enhanced resistance to infections, less asthma, and improved long-term respiratory outcomes.
We propose to conduct a Phase 2 clinical trial to evaluate rhCC10 in extremely premature infants (<29 weeks gestation) for the prevention of BPD and CRM. This will be a randomized, double-blind, placebo-controlled dose escalation study in 88 premature infants. A single intratracheal dose of study drug (rhCC10 or placebo) will be administered to preterm infants receiving surfactant and mechanical ventilation for treatment of RDS. Infants will be followed to evaluate safety, pharmacokinetics, and the short and long term efficacy of this approach. Safety will be evaluated through serious adverse event (SAE) and adverse event monitoring and by Bayley neurodevelopmental assessments at 18 months corrected gestational age (CGA). Efficacy measurements will include the primary combined endpoint of “alive without evidence of CRM at 12 months CGA” (defined by parental diaries and pulmonary questionnaires), comparing rhCC10 treated to placebo controls. The availability of a therapy which prevents lung injury, promotes lung development, and prevents serious respiratory infections and asthma in high risk preterm infants would be a highly significant advancement in care.
3. Antibiotic Safety in Infants with Complicated Intra-Abdominal Infections (SCAMP Trial).
Drs. Dammann, Davis, Smith. Funded by the National Institute of Child Health and Human Development (NICHD), supported by the Pediatric Clinical Network (PTN).
Recommended antibiotics for complicated intra-abdominal infections in infants include combinations of ampicillin, gentamicin, and cefotaxime with or without anaerobic coverage with metronidazole, piperacillin-tazobactam, or meropenem. In spite of their frequent use, the safety and efficacy of ampicillin, metronidazole, clindamycin, and piperacillin-tazobactam in infants with complicated intra- abdominal infections have not been established. The study is designed to evaluate the safety of 3 therapeutic regimens in premature infants (≤33 weeks GA) and 1 therapeutic regimen in late preterm and term infants (>34 weeks GA) with complicated intra-abdominal infections. This study will also evaluate the CSF PK of metronidazole, clindamycin, and piperacillin-tazobactam in infants with suspected or confirmed infections. The study design is a phase 2/3, prospective, open-label, randomized, multicenter, safety trial. Each participant receiving study drugs for complicated intra-abdominal infections (Groups 1–4) will participate in the study for up to 100 days. Participants receiving study drug for evaluation of CSF PK (Group 5) will participate in the study for up to 17 days. Enrollment for all groups is expected to last approximately 24 months. The rationale is that the most commonly used drugs in infants with complicated intra-abdominal infections are not labeled for use in this population because safety and efficacy data are lacking. The CSF PK for these drugs in this population is virtually non-existent. The proposed study will provide safety information required for labeling. In addition, the PK of the study drugs will be characterized in premature infants under an IND mechanism. Dose selection was determined using PK data from phase I trials in premature infants. In these trials, infant maturation was found to be significantly associated with drug clearance, requiring dosing modifications in this preterm population.
4. SUPPORT Study – Long-term Neurodevelopmental and Pulmonary Follow-up.
Drs. Dammann, Benjamin. Funded by the National Institute of Child Health and Human Development (NICHD).
The Surfactant Positive Airway Pressure and Pulse Oximetry Trial (SUPPORT) was a prospective, randomized, 2 x 2 factorial, multicenter trial conducted by the NICHD Neonatal Research Network to evaluate the efficacy of CPAP and a permissive ventilation strategy in combination with low (85-89%) or high(91-95%) oxygen saturation target ranges to lead to increased survival without bronchopulmonary dysplasia and retinopathy of prematurity among infants 24 – 26 6/7 weeks gestation. Children born this extremely preterm continue to have neurodevelopmental challenges in childhood. Many significant cognitive and performance problems can be seen within the first 2 years of life, but some cannot be delineated until school age. We continually look for tools to reliably predict outcomes. The SUPPORT Neuroimaging and Neurodevelopmental Outcomes Study is a prospective secondary study to the above-mentioned SUPPORT study. This study compares cranial ultrasounds at 4-14 days of life and 35-42 weeks post menstrual age and brain MRIs at 35-42 weeks post menstrual age among infants enrolled in the SUPPORT study. This study will allows us to assess the comparative and combined capabilities of early and late CUS and brain MRI to better predict long term and school-age neuromotor and neurodevelopmental outcomes. This cohort is currently being followed at 6 – 7 years of age to test the primary hypothesis that neonatal brain MRI is superior to ultrasound in predicting death after discharge or cognitive and neuromotor impairment at school age.
5. Sustained Aeration of Infant Lungs (SAIL) Trial.
Drs. Smith, Davis, Dammann, Maron. Funded by the National Institute of Child Health and Human Development (NICHD).
This is a multi-center, randomized, prospective study comparing positive pressure ventilation (PPV) and sustained inflation (SI) as resuscitation measures in the delivery room. PPV is standard of care in the USA, while SI breaths are standard of care in other parts of the world. Babies are eligible for this study if they are born between 23-26 6/7 weeks gestational age and require resuscitation at birth. The primary outcome is death or BPD (at 36 weeks postconceptual age). Neurodevelopmental data will also be collected at 2 years of age on these babies as part of secondary outcome analysis.
6. Bumetanide for Newborn Seizures - Pilot Study.
Dr. Davis; Funded by NIH.
This is a multi-center, randomized, double-blind controlled trial of bumetanide for the treatment of refractory neonatal seizures. This Phase I/II trial is designed to look at the feasibility, safety, and pharmacokinetics of bumetanide in newborns with hypoxic ischemic encephalopathy (HIE) or perinatal asphyxia, focal or multifocal stroke, or intracranial hemorrhage. Eligible patients are those who are 33 to 44 weeks post-menstrual age with a condition placing them at risk for neonatal seizures (perinatal asphyxia, hypoxic-ischemic encephalopathy, focal or multifocal stroke, or intracranial hemorrhage) or suspected clinical seizures. Once consent is obtained, continuous EEG monitoring will be initiated, if it has not already been started for clinical purposes. The EEG will be reviewed for seizure activity. If/when seizure activity is noted, study drug (bumetanide or placebo) will be ordered along with another dose of phenobarbital.
7. International Multicenter Randomized Placebo-controlled Trial to Investigate Dobutamine in the Treatment of Hemodynamic Insufficiency in the Immediate Postnatal Period.
Drs. Christiane Dammann, Olaf Dammann; funded by the European Union
Dobutamine is currently used off-label for the treatment of circulatory failure in neonates, in particular during the transitional phase after birth. Safety and efficacy data are limited for this indication. In this study, dobutamine is being evaluated for the treatment of neonatal circulatory failure in the first 72 hours after birth. In the first stage a new, age-appropriate drug formulation for dobutamine will be developed. A therapeutic observational study will then be conducted to optimize the design of a therapeutic confirmatory trial. Data from the observational study will contribute to decisions about which information available to the clinician should prompt treatment with dobutamine and modification of the dose administered. The observational study will include a pharmacokinetic sub-study. A dose-finding study will also be conducted once the parameters for dose-finding have been optimized. Finally, a randomized, placebo-controlled trial to generate safety and efficacy data for dobutamine in the transitional period following birth at extreme prematurity will be performed.