Our Research
Our Research
Explore the uncharted and fascinating biological world and make important scientific discoveries! Promote the growth and success of the next generation of scientists!
Our Goal
Our Goal
To understand metabolism and metabolic regulation in both normal physiology and disease states, and to apply this knowledge to human health and medicine.
Cardiac endocrinology
GDF15: A central question in physiology is how different organs communicate with each other to maintain whole-organism homeostasis. Research in the past 20 years revealed that non-glandular organs such as adipose tissue, liver and skeletal muscle can secrete hormones that regulate whole-body metabolism. In contrast, little is known regarding heart-derived hormones save for ANP and BNP, each discovered over 30 years ago. We recently discovered that Growth Differentiation Factor 15 (GDF15) is a new heart-derived hormone. Circulating GDF15 acts on the liver to inhibit growth hormone signaling and body growth. Plasma GDF15 is increased in children with concomitant heart disease and failure to thrive (FTT). Our results explain a well-established clinical observation that children with heart diseases often develop FTT.
We are currently using unbiased chemical and computational biology approaches (proximity labeling, etc.) to identify and study new heart-derived hormones in physiology and disease.
Single-cell genomics
We published one of the first massively parallel single-nucleus RNA-Seq (snRNA-Seq) studies in mammalian hearts. By profiling the transcriptome of ~24,000 nuclei, we identified major and rare cardiac cell types and revealed significant heterogeneity of cardiomyocytes, fibroblasts, and endothelial cells in postnatal developing hearts. When applied to a mouse model of pediatric mitochondrial cardiomyopathy, we uncovered profound cell type-specific modifications of the cardiac transcriptional landscape at single-nucleus resolution, including changes of subtype composition, maturation states, and functional remodeling of each cell type. Funded with several NIH and DOD grants, we are currently applying single-cell multiomics to understand metabolic and cardiac biology and disease.
Mitochondrial genomics and disease
Metabolic dysfunction directly causes or significantly contributes to many human diseases including heart disease, obesity, diabetes, cancer and aging. Most cells have limited capacity to store energy; therefore, cellular energy supply and demand must be coordinated. In addition, different cell types exhibit preference for specific metabolic pathways (fatty acid oxidation/FAO, glycolysis or oxidative phosphorylation/OxPhos). For instance, neurons rely on glycolysis and ensuing OxPhos but not FAO, while cardiomyocytes use OxPhos and FAO to generate most energy for cardiac contraction. However, it is little understood how specific metabolic pathways are coordinately regulated to support cell type-specific function. Work from my lab using cell type-specific KO mice and genomic approaches (ChIP-Seq and RNA-Seq) filled this knowledge gap by identifying the transcription factor estrogen-related receptor gamma (ERRγ) as a key transcriptional coordinator of cellular energy supply and demand. Mechanistically we showed that ERRγ directly regulates hundreds of OxPhos genes, and cooperates with distinct transcription factors to regulate cell type-specific metabolic (FAO) and functional genes. Accordingly, ERRγ is essential for normal cardiac contraction and conduction, neuronal function and learning/memory, and renal reabsorption. Together, these studies revealed how cellular energy production and consumption are elegantly coordinated in a cell type-specific manner. We are currently applying single-cell multiomics to further understand cell type-specific regulation of metabolic functions in metabolic, cardiac and mitochondrial disease.
Funding:
