Research Interest
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.
Molecular Mechanisms of Obliterative Vascular Remodeling in PAH
Pulmonary arterial hypertension (PAH) is a progressive, complex and devastating disease arising from a variety of pathogenic or genetic causes. Excessive vasoconstriction and abnormal vascular remodeling have been considered as the major factors contributing to the complicated pathogenesis of PAH. PAH types with different etiologies share several histopathological features including intima and media thickening, muscularization of distal pulmonary arteries, vascular occlusion, and complex plexiform lesions. However, the underlying mechanisms of obliterative vascular lesions remain unclear. Thus, identification of the critical molecular mechanisms mediating vascular remodeling are vital to inhibit and reverse the angioproliferative vascular remodeling in PAH.
HIF-2a Transcriptional Regulation in PAH
Pulmonary arterial hypertension (PAH) is a devastating respiratory disease leading to right-sided heart failure and premature death. Only modest improvements are achieved in PAH morbidity and mortality by treatment with the current anti-vasoconstriction drugs. Recent studies have highlighted the crucial role of endothelial activation of hypoxia inducible factor-2a (HIF-2a) but not HIF-1a in the pathogenesis of PAH and pharmacologic treatment with HIF-2a-selective inhibitor effectively inhibited experimental PAH. Here we propose to identify novel HIF-2a modulators and delineate the mechanisms of these molecules in regulating HIF-2a transcription activity. The longer term goal is development of novel therapeutic agents selectively targeting HIF-2α signaling for effective treatment of severe PAH, and thus promoting survival.
Single-Cell Technology to dissect cell heterogeneity
Utilizing the single-cell technology, we will be able to look into the specific cell heterogeneities in the disease pathogenesis of pulmonary vascular disease.
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Funding Sources
Our lab is currently funded by the Department of Internal Medicine, the University of Arizona College of Medicine-Phoenix, NHLBI R01, K99/R00 Award, American Heart Association Career Development Award, the Cardiovascular Medical Research and Education Fund, Arizona Biomedical Research Centre New Investigator Award.
Our lab was previously funded by the American Thoracic Society and Pulmonary Hypertension Association Foundation Grant, Arizona Biomedical Research Centre funding (ADHS18‐ 198871).
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