TIE 1 &oxygen sensitive pulmonary vascular development

Childrens Hospital Of Philadelphia, Philadelphia PA

Investigators

Linked publications & trials

Abstract

(Applicant's Abstract) Bronchopulmonary dysplasia (BPD) has traditionally been viewed as severe lung injury resulting from mechanical ventilation and oxygen exposure. However, increasing evidence suggests that an arrest of normal lung epithelial and vascular development is at least partially responsible for the pulmonary defects currently seen in small premature infants. Very little is know about the mechanisms regulating normal pulmonary vascular development and even less is known about aberrant pathways of vascular development that may contribute to the pathology of BPD. While vascular development in the embryo is thought to be mediated by several members of the tyrosine kinase family of cell surface receptors, recent genetic evidence documents that one of these receptors, Tiel, is essential for latter stages of embryonic vascular development and preferentially required for development of a mature pulmonary circulation. The investigators have recently documented both accentuated Tiel expression during critical periods of pulmonary vascular development and attenuated expression in response to hyperoxia in the adult. They hypothesize that Tie1 plays an essential role in oxygen sensitive pulmonary vascular development by promoting the transition from a proliferative to a quiescent endothelial phenotype and in maintaining endothelial quiescence in the maturing lung. Furthermore, they propose that disruption of Tiel expression is responsible, at least in part, for the defects in vascular development detected in BPD. The investigators propose to: 1) Determine the role of Tiel in prenatal pulmonary vascular development by comparing the response to hypoxia (embryonic normoxia) of lung explants isolated from wild type, heterozygous, and Tie-1 null mutant embryos and 2) Define the role of Tiel in early postnatal pulmonary vascular development in vivo by utilizing a conditional null mutation of the Tie1 allele in conjunction with PECAM antibody mediated pulmonary endothelial specific immunotargetting of Cre recombinase to investigate the effects of attenuated Tiel expression on acute vascular response to hyperoxia in the newborn mouse. Finally, they will 3) identify down stream targets of Tiel activation during pulmonary vascular development using laser capture microdissection to isolate pulmonary endothelial cells in situ from lungs of wild type and Tiel null mutant embryos for solution subtraction hybridization to identify genes that are enhanced or suppressed in response to Tiel activation. The investigators will compare the results seen in our murine model to those detected in the mechanically ventilate lamb model presented in Project V and determine if delineated alterations are recapitulated in premature infants through collaborations with the Clinical Core (B). Upon completion, these experiments will further define the role of Tiel in pulmonary ontogeny and define critical Tiel mediated molecular pathways regulating oxygen sensitive pulmonary vascular response relevant to the developmental vascular pathology of BPD.