The research interests in Yang lab spans from basic science targeting fundamental mechanisms underlying human diseases, to translational medicine aiming at advancing the diagnosis and treatment of human illness. Our current research programs focus on identifying novel mediators/pathways that mediate cardiac/non-cardiac organ fibrosis, cardiomyopathy, atherosclerosis and cardiac regeneration.

Identifying novel mediators of organ fibrosis as new therapeutic targets
Exploiting a combined approach of RNASeq-based bioinformatics, molecular, cellular and animal studies, we have discovered multiple novel molecular determinants, including long noncoding RNAs and ER-resident protein TXNDC5, which contribute critically to the development of cardiac fibrosis and cardiomyopathy. These results not only shed new lights on the pathogenesis of cardiovascular diseases, but also hinting a novel therapeutic opportunity by targeting these pathogenic mediators/pathways. Our research has yielded multiple high-impact publications in the field of cardiovascular research, including Circulation (Circulation 2014), Circulation Research (Circ Res 2015, 2018) and Nature Communications (2020, in press). Now we are ready to extend our research findings to tackle atherosclerosis, cardiac arrhythmias, as well as to fibrotic disorders involving non-cardiac organs and tumorigenesis.

Deciphering the functional roles of non-coding RNAs in cardiovascular diseases
One of the research focuses in Yang lab is to explore the functional roles of non-coding RNAs, specifically long non-coding RNAs (lncRNA) and snoRNAs, in myocardial diseases and cardiac arrhythmias. Using next-generation sequencing technology, we have completed a comprehensive cardiac transcriptome profiling in human non-failing and cardiomyopathic samples, and have identified distinctive expression pattern and putative functions of hundreds of human cardiac lncRNAs and snoRNAs that are involved in the pathogenesis of cardiomyopathy. By combining comparative genomics and molecular genetics in cellular and animal models, we are beginning to uncover the molecular functions of several interesting lncRNAs and snoRNAs that are involved in myocardial fibrosis, cardiac hypertrophy and electrical remodeling. We are also applying CRISPR (clustered regularly interspaced short palindromic repeats) genome editing technology to control lncRNA expression levels in vitro and in vivo to advance our understanding of the functional roles of various cardiac lncRNAs and snoRNAs. In addition, we are exploring the possibility of using myocardial and circulating lncRNAs as the biomarkers for cardiovascular disease diagnosis and outcome prediction.

Mitochondrial oxidative stress, gap junction remodeling and cardiac arrhythmias
Oxidative stress has been shown to play a critical role in the pathogenesis of cardiac hypertrophy, heart failure and arrhythmias. It has been discovered that increased mitochondrial reactive oxidative species (mitoROS) is responsible for cardiac gap junction protein connexin 43 (Cx43) downregulation, slow conduction and increased arrhythmogenecity in response to enhanced renin-angtiotensin system (RAS) activity. Our recent work has shown that increased cardiac RAS signaling leads to eNOS-mediated caveolin 1 (Cav1) S-nitrosation, decreased Cav1-cSrc interaction, cSrc activation and increased Cx43 degradation. Pharmacological inhibition of mitoROS or cSrc tyrosine kinase abrogates RAS-induced Cx43 downregulation, conduction abnormality and arrhythmias.  We are currently exploring the molecular mechanisms transducing RAS signaling to increased mitoROS production, as well as the intriguing molecular function of eNOS in sensing cellular redox status and modulating the electrical functioning in the cardiomyocytes.