Research

Research 

Our Philosophy: Good science and good scientists.  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: To understand metabolism and metabolic regulation in both normal physiology and disease states, and to apply this knowledge to human health and medicine. 

Our Research:

1. Cardiac endocrinology
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. More importantly, these studies reveal a new endocrine mechanism by which the heart coordinates cardiac function and body growth. Plasma GDF15 was recently shown to be elevated in patients with various heart diseases and is associated with increased morbidity and mortality. However, how GDF15 is increased in heart disease remains unclear. We tackled this clinically important question and identified the whole gene regulatory network that induces GDF15 transcription in heart disease, using massively parallel single-nucleus RNA-Seq (~20,000 nuclei). This study also revealed for the first time the organ composition, cell type and heterogeneity in normal postnatal, developing mouse heart, and the profound changes of transcriptional landscape of every cell type in the disease state. In addition, we have identified the key enzymes that process GDF15 pro-hormone into its mature form. Together, these studies helped pioneer a new field of cardiac endocrinology.


Hu P, Liu J, Zhao J, Wilkins BJ, Lupino K, Wu H, Pei L. (2018). Single-nucleus transcriptomic survey of cell diversity and functional remodeling in the postnatal developing hearts. Genes & Development, in press.
Li J, Liu J, Lupino K, Liu X, Zhang L, Pei L. (2018). GDF15 maturation requires proteolytic cleavage by PCSK3, 5 and 6. Molecular and Cellular Biology.
Wang T, Liu J, McDonald C, Lupino K, Zhai X, Wilkins BJ, Hakonarson H, Pei L. (2017). GDF15 is a heart-derived hormone that regulates body growth. EMBO Mol Med

Ongoing projects:
a) Single cell analysis of postnatal mouse hearts to understand how heart disease affects cardiac functions at single cell level;
b) Single cell analysis to mechanistically understand specific disease conditions that induce GDF15 transcription;
c) Investigating how heart disease impacts GDF15 maturation through regulating the activity of GDF15 processing enzymes PCSK3, 5 and 6.
d) Identify the liver GDF15 receptor and elucidate its signaling pathway in the liver.


2. Cell type-specific regulation of cellular metabolism
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.

Wang T, McDonald C, Petrenko NB, Leblanc M, Giguere V, Evans RM, Patel VV, Pei L. (2015). Estrogen-related receptor alpha (ERRalpha) and ERRgamma are essential coordinators of cardiac metabolism and function. Molecular and Cellular Biology
Pei L*, Mu Y, Leblanc M, Alaynick W, Barish GD, Pankratz M, Tseng TW, Kaufman S, Liddle C, Yu RT, Downes M, Pfaff SL, Auwerx J, Gage FH, Evans RM. (2015). Dependence of Hippocampal Function on ERRgamma-Regulated Mitochondrial Metabolism. Cell Metabolism (*cocorresponding author)
Zhao J, Lupino K, Wilkins BJ, Qiu C, Liu J, Omura Y, Allred AL, McDonald C, Susztak K, Barish GD, Pei L. (2018). Genomic integration of ERRgamma-HNF1beta regulates renal bioenergetics and prevents chronic kidney disease. PNAS.

Ongoing projects:
a) Modulating ERRγ activity to prevent/ameliorate kidney disease;
b) Modulating ERRγ activity to prevent/ameliorate mitochondrial disease using human iPS cell and animal models.
Funding 

 



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