Research Interests and Projects
Single-cell and Spatial Transcriptomics to Understand Lung Disease Pathogenesis
General Capillary ECs transit into Arterial ECs
Our recent single-cell RNA sequencing, spatial transcriptomics analysis, RNASCOPE, and immunostaining analysis showed that arterial ECs accumulation and loss of capillary ECs were evident in human PAH patients and pulmonary hypertension (PH) rodents. Pseudotime trajectory analysis of the single-cell RNA sequencing data suggest that lung capillary ECs transit to arterial ECs during the development of PH. Our study also identified CXCL12 as the marker for arterial ECs in PH. Capillary EC lineage tracing approach using capillary specific-Dre;Tdtomato reporter mice demonstrated that capillary ECs gave rise to arterial ECs during PH development. Genetic deletion of HIF-2a or pharmacological inhibition of Notch4 normalized the arterial programming in PH. In conclusion, our study demonstrates that capillary endothelium transits to arterial endothelium through the HIF-2a-Notch4 pathway during the development of PAH. Thus, targeting arterial EC transition might be a novel approach for treating PAH patients. This work is funded by NIH R01 grant.
Lineage Tracing Approach to Dissect Pulmonary Vascular Remodeling
With identification of a novel mouse model with severe PAH, Egln1Tie2Cre mice, we have developed a powerful tool for use to trace different cell populations (such as endothelial cells, smooth muscle cells, fibroblast, etc) in our model system. A major advantage of this model is mincing human PAH pathology, which allows it to study dynamic change of cells contributing to the severe pulmonary vascular remodeling in PAH.
Role of Sox17 in the Pathogenesis of PAH
Pulmonary arterial hypertension (PAH) is characterized by progressive increase of pulmonary vascular resistance and obliterative pulmonary vascular remodeling that result in right heart hypertrophy, failure, and premature death. The underlying mechanisms of vascular remodeling and obliterative vascular lesion formation remain unclear. Genetic mutations and variants were found in patients with idiopathic PAH and PAH with congenital heart disease. However, the mechanistic role of endothelial SOX17 in regulating pulmonary vascular remodeling in the pathogenesis of PAH has not been reported. We hypothesize that endothelial SOX17 deficiency contributes to the pathogenesis of PH. We will 1) define the novel role of endothelial SOX17 in the pathogenesis of PH using multiple transgenic mouse and rat models. 2) delineate the molecular mechanisms downstream of endothelial SOX17 deficiency in mediating pulmonary vascular remodeling and PAH and 3) explore the translational potential of targeting SOX17 signaling. Completing our proposed study will provide a novel therapeutic strategy for the effective treatment of PAH in patients. This work is funded by NIH R01 Grant.
Fatty acid metabolism in PAH
Fatty acid metabolism dysfunction is linked to PAH. However, the mechanistic role of fatty acid metabolism in regulating pulmonary vascular remodeling in the pathogenesis of PAH has not been reported. We hypothesize that endothelial FABP4/5 signaling regulates fatty acid transport and metabolism which contributes to severe vascular remodeling in the pathogenesis of PAH. This work is funded by AHA CDA grant and NIH R01 grant.