The applicant's goal is to become an independent physician-scientist who engages in basic research that has clinical relevance. The applicant has obtained research training in molecular and cellular biology, and completed her fellowship training in Neonatology, and now is a faculty member in the Division of Neonatology. This proposal will provide the applicant with the opportunity to expand her scientific skills through a unique integration of interdepartmental resources. Her research will focus on understanding the role of connective tissue growth factor (CTGF) in normal and deranged lung morphogenesis. Bronchopulmonary dysplasia (BPD), a common long-term pulmonary sequelae of premature infants, is thought to arise as a consequence of developmental arrest of the immature lung in response to injury and abnormal repair. Transforming growth factor-beta (TGF-beta)is a key negative regulator of branching morphogenesis and is increased in lungs of infants at risk for BPD. CTGF expression is selectively induced by TGF-beta in fibroblast cells. Inhibition of CTGF synthesis or action can completely block TGF-beta stimulated fibroblast proliferation, collagen synthesis and induction of alpha-smooth muscle actin (alpha-SMA), a characteristic marker of myofibroblasts. Our preliminary studies using a mouse embryonic lung explant culture model have demonstrated that CTGF inhibits branching morphogenesis, TGF-beta induces CTGF protein expression in mesenchymal cells and concomitantly inhibits branching morphogenesis. Blocking of CTGF action with an anti-CTGF antibody attenuated TGF-13 inhibition of branching morphogenesis. Our hypothesis is that CTGF is a negative regulator of branching morphogenesis and mediates TGF-beta inhibition of branching morphogenesis. We speculate that inhibition of CTGF biological activity may be of therapeutic benefit to premature infants at risk of BPD.
The specific aims are: 1). To determine the molecular and cellular responses involved in CTGF inhibition of branching morphogenesis in lung explant culture. 2). To evaluate the effects of blocking CTGF action or synthesis on TGF-beta inhibition of branching morphogenesis. 3). To investigate the role of CTGF in lung morphogenesis in vivo by over-expression of CTGF in airway epithelium of transgenic mice. The results of this proposal will expand our fundamental knowledge of developmental lung biology and provide the foundation for experiments to evaluate the role of CTGF in an animal model of BPD. This may contribute new insights into the prevention and management of BPD. The proposed research training plan will also include participation in didactic courses, seminars, formal presentations at local and national meetings, as well as regular reviewing of the candidate's progress by the advisory committee. It is expected that this award will allow the PI to become an independent investigator in the area of perinatal lung biology.
