Bronchopulmonary dysplasia (BPD) is a common disease afflicting premature newborns who receive mechanical ventilation and oxygen therapy. In the United States, there are more than 500,000 babies born prematurely each year, of which ~ 49,000 are BPD patients. The pathology of BPD is consistent with an arrest of lung development, characterized by impaired angiogenesis and alveolarization. Importantly, the defects of lung development in BPD patients cause persistent impaired lung function in adulthood, leading to pulmonary arterial hypertension (PAH) and chronic obstructive pulmonary disease (COPD). The underlying mechanisms of BPD are still unknown and the current therapy is not effective. The objectives of the current proposal include: 1. Reveal novel mechanisms of pathogenesis of hyperoxia treated mice (BPD mouse model). 2. Provide new therapeutic strategies of hyperoxia treated mice. Since both endothelial cell (EC) specific G protein-coupled receptor kinase 2-interacting protein-1 (GIT1) knockout (ecGIT1-KO) mice and hyperoxia treated mice resemble BPD, these two mouse models are ideal tools to study the mechanisms of BPD. Our preliminary data demonstrate that there is enhanced Delta like 4(Dll4) mediated Notch signaling in lungs of both models. Notch signaling is strictly cell type and context dependent. Our findings also imply that Dll4 activates Notch4 in EC to inhibit angiogenesis, while Dll4 activates Notch1 in airway epithelium cell (AEC) to inhibit alveolarization through EC-EC and EC-AEC crosstalk. These inhibitory effects possibly occur through decreased cell proliferation and cell survival. Based on these exciting findings, we hypothesize that enhanced Dll4 mediated Notch signaling contributes to the angiogenesis and alveolarization in BPD as modeled by ecGIT1-KO mice and hyperoxia treated mice. To test our hypothesis, three Aims are proposed.
Aim 1 : Determine the functions and mechanisms of EC-EC and EC-AEC crosstalk initiated by Dll4 mediated Notch signaling in ecGIT1-KO mice.
Aim 2 : Define Dll4 mediated Notch1/4 signaling in hyperoxia treated mice.
Aim 3 : Evaluate the therapeutic effects of inhibiting Dll4 on lung development of hyperoxia treated mice. Accomplishing the aims of the proposal will fill the specific knowledge gap regarding mechanisms of postnatal lung development and pathogenesis of hyperoxia related lung dysfunction. We also intend to discover novel therapeutic strategies for BPD and related lung diseases, such as COPD and PAH. Broadly, the results will provide insight into mechanisms of both normal and pathologic angiogenesis that may be important in cancer, diabetes, ischemic cardiac and cerebral vascular disease.
This proposal will reveal novel mechanisms of postnatal lung development and pathogenesis of hyperoxia treated mice mediated by Dll4-Notch signaling. We also may provide novel therapeutic strategies for related lung diseases, pulmonary arterial hypertension and chronic obstructive pulmonary disease.
|Majumder, Syamantak; Zhu, GuoFu; Xu, Xiangbin et al. (2016) G-Protein-Coupled Receptor-2-Interacting Protein-1 Controls Stalk Cell Fate by Inhibiting Delta-like 4-Notch1 Signaling. Cell Rep 17:2532-2541|