This new investigator proposal describes a 5 year training program for the development of a physician scientist career in Neonatal and Perinatal Medicine. This investigator has completed a Ph.D. in developmental biology, a clinical fellowship in neonatology, and is currently an Instructor in the Division of Neonatology. In carrying out the proposed research, the principle investigator will acquire expertise in transgenics, histology, and genomics. Dr. Aaron M. Zorn, an Associate Professor from the Division of Developmental Biology, will mentor the principal investigator's scientific development. Dr. Zorn is a recognized leader in the field of foregut organ development. An advisory committee of outstanding, internationally recognized medical scientists will provide scientific and career advice. The Perinatal Institute, Division of Neonatology, and Division of Developmental Biology at Cincinnati Children's Hospital Medical Center are committed to providing an ideal training setting by incorporating the required expertise from diverse resources across divisions to ameliorate neonatal and pediatric disease. The proposed experiments and research environment will maximize the potential for the principal investigator to establish a scientific niche and develop an academic career. Research will focus on the development and maintenance of foregut- and lung-specific progenitors.
Specific Aims will test a model where BMP signaling first positively promotes foregut identity and induces sizzled expression. szl and twisted gastrulation then act as BMP feedback inhibitors to temporally and/or spatially restrict BMP ligand activity. This restriction is required to maintain foregut progenitors. Hours later a second wave of BMP signaling segregates the organ lineages with crossveinless-2 mediating BMP down- modulation to establish the lung anlage. The proposed experiments will determine the precise signaling dynamics and the role of the secreted factors during foregut and subsequent lung progenitor development.
The specific aims i nclude: 1) Determine whether two discrete waves of BMP activity are required to maintain foregut and subsequent organ-specific progenitors. 2) Test hypothesis that extracellular BMP modulators sizzled and twisted gastrulation are required to maintain foregut progenitors by reducing an initial wave of BMP signaling, and 3) Test hypothesis that extracellular BMP modulator crossveinless-2 is required to specify lung lineage by reducing a second wave of BMP signaling. This will be the first to detail a functional requirement for BMP inhibitory mechanisms in the developing foregut and lung progenitors. This proposed research will increase our understanding of fetal organ induction and thus inform our clinical perspective on neonatal foregut organ malformation (tracheoesophageal fistula), injury (such as during respiratory distress syndrome), and repair (such as during healing from bronchopulmonary dysplasia). Furthermore, it will enhance strategies to more efficiently differentiate human ES cells into therapeutically useful foregut organ tissues.
Congenital foregut malformations are a devastating, costly, and poorly understood pathology because the molecular basis of foregut organ formation remains unresolved. I test a novel hypothesis that dynamic Bone Morphogenetic Protein (BMP) signaling activity waves are regulated by essential, extracellular BMP modulators during foregut organ development. The findings from this proposed research will provide both critical new insights into normal foregut organ development as well as new molecular targets relevant to foregut malformation, lung injury/repair mechanisms, and foregut organ differentiation from human embryonic stem cells.
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