Bronchopulmonary dysplasia (BPD) has traditionally been viewed as severe lung injury but increasing evidence suggests that an arrest of normal lung development is at least partially responsible for this pathology frequently seen in premature neonates. While much is known about epithelial differentiation, very little is known about the mechanisms regulating normal pulmonary vascular development and even less is known about how aberrant pathways of vascular development may contribute to the pathology of BPD. Genetic evidence documents that Tie1, an endothelial receptor tyrosine kinase, is preferentially required for development of a mature pulmonary circulation. We have recently documented accentuated expression of Tie 1 during critical periods of pulmonary vascular development, increased expression in embryonic lung in response to hypoxia, and attenuated expression in response to hyperoxia in the adult animal. We hypothesize that Tiel plays an essential role in oxygen sensitive pulmonary vascular development by promoting the transition from a proliferative to a quiescent endothelial phenotype and thus may be involved in development of BPD. We propose to: 1) Determine the role of Tie l in prenatal vascular development utilizing a Tie l-lacZ knock in/knock-out reporter mouse to evaluate the effects of embryonic normoxia (standard hypoxia) on lung explant cultures and a renal allograft model to study latter stages of fetal development 2) Define the role of Tie 1 in postnatal pulmonary vascular development in vivo using conditional deletion of the Tie 1 allele and hyperoxic challenge and 3) Identify down stream targets of Tie l activation during pulmonary vascular development using FACS sorting and laser capture microdissection to isolate pulmonary endothelial cells from lungs of wild type and Tie l null mutant embryos in conjunction with microarray analysis to identify genes that are enhanced or suppressed in response to Tie l expression. Upon completion, these experiments will have further defined the role of Tie l in pulmonary vascular ontogeny and delineated critical Tie l mediated molecular pathway(s) regulating oxygen sensitive pulmonary vascular injury relevant to the developmental vascular pathology of BPD.
| DeLaughter, Daniel M; Clark, Cynthia R; Christodoulou, Danos C et al. (2016) Transcriptional Profiling of Cultured, Embryonic Epicardial Cells Identifies Novel Genes and Signaling Pathways Regulated by TGF?R3 In Vitro. PLoS One 11:e0159710 |
| Woo, Kel Vin; Baldwin, H Scott (2011) Role of Tie1 in shear stress and atherosclerosis. Trends Cardiovasc Med 21:118-23 |
