Specialty Division

Cancer and Immunobiology

Research Expertise

Cardiac Endocrinology; single-cell biology; Mitochondrial Function and Metabolic Disease

The overall goal of the lab is to understand how different organs react to energy cues and communicate with each other to maintain whole-organism homeostasis in both physiological and pathological contexts. We welcome postdoctoral fellows and (rotating) graduate students to join us in 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 40 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 actively understanding the biology of GDF15 as it has become an important therapeutic target for metabolic disease and cancer cachexia with clinical trials ongoing. More importantly, we are using proximity labeling in vivo to identify and understand new heart-derived hormones in physiology and disease, a new area of research of cardiac endocrinology.

Zhao J, Pei L (2020). Cardiac Endocrinology: Heart-derived hormones in physiology and disease. JACC Basic Transl Sci.
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.
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/rotation projects:
a) Proximity labeling in vivo to identify new heart-derived hormones and understand their biological function;
c) Understand GDF15 biology;
d) Identify the liver GDF15 receptor and elucidate its signaling pathway in the liver.

2. Single cell multiomics to understand metabolic and cardiac biology and disease.
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.

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.

Ongoing/rotation projects:
a) Building a multidimensional atlas of the human heart - NIH Human Biomolecular Atlas Program (HuBMAP);
c) Single-cell multiomics to understand Fontan-associated liver disease;
d) Single-cell multiomics to understand cell-type specific metabolic changes in heart disease.

3. Cell type-specific regulation of mitochondrial function
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.

Pei L, Wallace DC (2018). Mitochondrial Etiology of Neuropsychiatric Disorders. Biological Psychiatry.
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.
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)
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

Ongoing/rotation 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.
c) Single-cell multiomics to understand cell-type specific cardiac metabolic changes in heart disease.
d) Single-cell multiomics to understand how mitochondrial heteroplasmy affect nuclear transcriptome and epigenome.

Itmat Expertise

Metabolic regulation, mitochondrial function and human disease

Graduate Groups

Cell and Molecular Biology

Education

B.S. University of Science and Technology of China, 2000
Ph.D. UCLA, 2006

Specialty Certification

Postgraduate Training

Postdoctoral Fellowship, Howard Hughes Medical Institute, Gene Expression Laboratory, Salk Institute for Biological Studies, 2006-2013

Awards and Honors

Guo Moruo Scholarship, University of Science and Technology of China, 2000
George J. Popjak Scholar, UCLA School of Medicine, 2005
NIDDK Scholarship, Keystone Symposia, 2005
Sarkaria Award, UCLA School of Medicine, 2006
Parker B. Francis Fellowship, 2009
Fellow, American Heart Association (AHA), 2021

Memberships and Professional Organizations

American Heart Association, 2006 - Present
Society of Chinese Bioscientists in America, 2015 - Present
International Society for Heart Research (ISHR), 2020 - Present
American Association for the Advancement of Science (AAAS), 2021 - Present

Web Links

Selected Publications