Status: Funded - Closed
Clinical and molecular analysis of congenital pulmonary airway malformations
Daniel Swarr, M.D.
BACKGROUND: Despite their tremendous impact on pediatric health, the etiology of many of these disorders remains poorly defined. Without understanding the underlying cause of these disorders, we are greatly limited in our ability to improve diagnostic testing and develop novel therapeutic strategies.
GAP: This study will identify gene expression changes in CPAMs, the underlying molecular defects leading to these changes, and how these findings result in variable clinical outcomes, providing the basis for improved diagnostic testing and rationale therapeutic design.
Hypothesis 1: CPAMs result from disruption of the basic signaling pathways regulating lung branching morphogenesis (e.g. FGF, Wnt signaling), and that each subtype of CPAM has distinct patterns of altered gene expression.
Hypothesis 2: Altered gene expression patterns observed in CPAMs are the direct consequence of post-zygotic somatic mutations originating in key regulatory genes within these basic signaling pathways during lung development.
Hypothesis 3: Rate of CPAM size progression during fetal development, lesion subtype, and overall clinical severity will correlate with specific patterns of gene expression.
METHODS: This case-control study will compare gene expression changes in CPAM lesions to each patient’s own healthy lung tissue as an internal control; these changes will ultimately be correlated with clinical outcome. Infants undergoing surgical resection of a congenital pulmonary airway malformation (CPAM), for whom leftover lung tissue will be available for collection, will be eligible to participate.
IMPACT: These data will provide the basis for the development and testing of targeted therapeutic agents in animal models of CPAMs, and will provide a framework for identifying the etiology of other structural congenital malformations, knowledge that is often therapeutic, in and of itself, for families of infants affected with these disorders.
The Children's Hospital of Philadelphia