|  Mary Elizabeth Sunday, M.D., Ph.D.
Mary Elizabeth Sunday, M.D., Ph.D.
Professor,
Department of Pathology
Duke University Medical Center
Box 3712
Durham, NC 27710
Phone: 919-684-2452
e-mail: Mary.Sunday@Duke.Edu The Sunday Laboratory is dedicated to opening new avenues of exploration in lung development and lung developmental pathobiology. First, there is a vision to identify early causes of lung disease, both in newborns and in adults, seeking specific molecular targets for novel treatments to prevent injury. Second, there are ground breaking basic science investigations of early molecular mechanisms of lung development.
LUNG PATHOBIOLOGY
For over 12 years, the Sunday Laboratory has been studying bronchopulmonary dysplasia (BPD), a chronic lung disease of premature newborns that is a major unsolved medical problem. The Laboratory identified an initiating cause of BPD as bombesin-like peptide (BLP) overproduction by pulmonary neuroendocrine cells.
 |  |  | | Bombesin was first discovered in skin of the frog, bombina bombina. | Highest levels of bombesin-like peptide occur in neuroendocrine cells of fetal lung. Levels usually drop by birth. | 30% of premature infants born at = 28weeks develop BPD. BLP overproduction shortly after birth confers a 10-fold increased risk of BPD, the highest risk yet identified. |
Urine BLP levels are significantly elevated in newborns who later develop BPD, the magnitude of the increase being directly proportional to the degree of lung injury. In human infants, a single elevated BLP level during the first five postnatal days confers a tenfold increased risk of developing BPD. Most importantly, treatment of high-risk newborns with anti-BLP monoclonal antibodies prevents the progression to lung injury and arrested alveolar development.
Recently, the Sunday Laboratory determined that anti-BLP monoclonal antibodies also reverse thymic abnormalities and autoimmune anti-lung T-cell responses that they identified in BPD animals. This was the first demonstration that adaptive immunity contributes to lung injury in BPD. In summary, BLP blockade prevents both acute and chronic lung injury and permits the progression of normal alveolar development.
A current goal of the Sunday Laboratory is to carry out a clinical trial for preventing BPD using a novel small molecule inhibitor of BLP, 77427, which is the drug of choice in humans because it binds BLP with the same affinity as the murine monoclonal antibody but it does not pose any risk for immune complex disease. After testing 77427 in an animal model, the Laboratory will initiate Phase I trials in infants born at or before 28 weeks gestation.
The Sunday Laboratory is also investigating the role of BLP in the pathophysiology of radiation-induced lung injury, adult respiratory distress syndrome (ARDS), lung transplant rejection, and asthma. The Laboratory has demonstrated that ARDS patients have markedly elevated BLP levels. High BLP levels are known to occur in smokers who progress to chronic obstructive pulmonary disease. Future research goals include using BLP blockade to prevent ARDS, smoking-related lung disease, lung transplant rejection, and asthma.
LUNG DEVELOPMENT
Genetic analysis of the Drosophila tracheal system led to the discovery of a novel gene, trachealess (trl) was discovered in a large-scale screen for embryonic lethal mutations. TRL-null Drosophila embryos have complete absence of the trachea, which is the fly respiratory system. The Sunday Laboratory cloned the murine homologue of trl using degenerate oligonucleotide probes to consensus domains of Drosophila trl, and identified this homologue as NPAS3. The Sunday Laboratory then generated an NPAS3-null mouse that is now in the process of being characterized. Thus far, it is known that over 90% of the homozygous knockout mice die within a few hours after birth, with severely emphysematous lungs. The heterozygous knockout mice also have severely emphysematous lungs but these mice survive and are fertile. Pulmonary function testing of the NPAS3-knockout mice (both homozygous and heterozygous) shows overexpanded lungs with increased airway reactivity, consistent with emphysema and bronchoconstriction.
Future research goals are to determine the cellular and molecular mechanisms by which NPAS3 regulates normal lung development, and to determine how NPAS3 deficiency might contribute to emphysema and asthma caused by smoking cigarettes.
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