Education & Training
- B.S. Massachusetts Institute of Technology, Biology-1995
- Ph.D., University of California, Biomedical Sciences-2001
- M.D., University of Callifornia, Medicine-2003
Research Interest Summary
We are a basic science and translational research group studying the molecular mechanisms of pulmonary vascular disease and pulmonary hypertension (PH) – an example of an enigmatic disease where reductionistic studies have primarily focused on end-stage molecular effectors. To capitalize on the emerging discipline of "network medicine," our research utilizes a combination of network-based bioinformatics with unique experimental reagents derived from genetically altered rodent and human subjects to accelerate systems-wide discovery in PH. Our published findings were among the first to identify the systems-level functions of microRNAs (miRNAs), which are small, non-coding RNAs that negatively regulate gene expression, as a root cause of PH. Our lab developed novel in silico approaches to analyze gene network architecture coupled with in vivo experimentation. The results now offer methods to identify persons at-risk for PH and develop therapeutic RNA targets. This work is the cornerstone of our evolving applications of network theory to the discovery of RNA-based origins of human diseases, in general.
Defining the network biology of non-coding RNAs in pulmonary hypertension. To capitalize on the emerging discipline of "network medicine," our research has recently utilized a combination of network-based bioinformatics with unique experimental reagents derived from genetically altered rodent and human subjects to accelerate systems-wide discovery in PH. In doing so, our published work has been among the first to identify the crucial importance of microRNAs (miRNAs) in processes critical to PH progression. We have focused on the prediction and confirmation of how the PH gene network is globally controlled by miRNAs and other non-coding RNAs (i.e., lncRNAs), thus impacting vascular phenotypes in rodents and humans in vivo. With such a foundation, we aim to prove that combining network theory with experimental validation can accelerate systems-wide discovery and therapeutic strategy, by identifying novel disease genes, their roles within interconnected molecular processes, and the comprehensive response of those connections to pharmacologic interventions.
Studying the molecular regulation of mitochondrial metabolism by microRNAs. We have a keen interest in identifying mechanisms by which microRNAs control mitochondrial metabolism in hypoxia and in hypoxia-relevant diseases such as pulmonary hypertension (PH). Specifically, we identified the hypoxia-dependent microRNA, miR-210, as a regulator of the ISCU gene and thus essential for iron-sulfur biogenesis. Under acute hypoxia, such activity facilitates the shift of oxidative mitochondrial phosphorylation to glycolysis. Thus, our findings provided a fundamental understanding of the so-called “Pasteur” effect which improves cellular survival during hypoxic injury. We have extended these observations to prove that the miR-210-ISCU axis controls the metabolic dysregulation in PH pathogenesis in both human and rodent examples of disease. Importantly, we have also identified a new human cohort of patients carrying genetic mutations of ISCU who suffer from exercise-induced PH. Together, these findings establish iron-sulfur deficiency as a powerful and novel metabolic origin of PH, a new therapeutic target for PH, and perhaps, a foundation for discovery in other diseases that share similar pathogenic and metabolic underpinnings.
Defining the regulation of circulating microRNAs in hypoxia and exercise. We have been studying the biology of extracellular miRNAs in hypoxia and exercise. We were the first to establish a specific mechanism by which the Argonaute 2 protein can coordinate release and activity of miRNAs such as miR-210 under hypoxic stress. In translational studies, we were also the first to report the specific and dynamic regulation of plasma-based circulating miRNAs in states of acute and endurance exercise. Together, these findings suggest the biologic importance of circulating miRNAs in hypoxia and exercise and set the stage for greater in-depth analysis of the functions of these versatile molecules.
Chan SY, Zhang YY, Hemann C, Mahoney CE, Zweier JL, Loscalzo J. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism. 2009; 10 (4); 273 – 84. Pubmed PMID: 19808020; PMCID: PMC2759401.
Baggish AL, Hale A, Weiner RB, Lewis GD, Systrom D, Wang F, Wang TJ, Chan SY (Senior Author). Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. Journal of Physiology. 2011; 589(Pt 16):3983-94. Pubmed PMID: 21690193; PMCID: PMC3179997.
Parikh VN, Jin RC, Rabello S, Gulbahce N, White K, Hale A, Cottrill KA, Shaik RS, Waxman AB, Zhang YY, Maron BA, Hartner JC, Fujiwara Y, Orkin SH, Haley KJ, Barabasi A-L, Loscalzo J, Chan SY (Senior Author). MicroRNA-21 Integrates Pathogenic Signaling to Control Pulmonary Hypertension: Results of a Network Bioinformatics Approach. Circulation. 2012; 125(12):1520-1532. Pubmed PMID: 22371328; PMCID: PMC3353408.
Featured Commentary: Ahmad F, Champion HC, Kaminsky N. Towards systems biology of pulmonary hypertension. Circulation. 2012; 125(12):1477-1479. Pubmed PMID:22371329 (Commentary).
Bertero T, Lu Y, Annis S, Hale A, Bhat B, Saggar R, Saggar R, Wallace WD, Ross DJ, Vargas SO, Graham BB, Kumar R, Black SM, Fratz S, Fineman JR, West JD, Haley KJ, Waxman AB, Chau BN, Cottrill KA, Chan SY (Senior Author). Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. Journal of Clinical Investigation. 2014; 124(8):3514-3528. (Recommended in F1000Prime as being of special significance in its field). Pubmed PMID: 24960162; PMCID: PMC4109523.
Hale A, Lee C, Annis S, Min, PK, Pande R, Creager MA, Julian CG, Moore LG, Mitsialis SA, Hwang SJ, Kourembanas S, Chan SY (Senior Author). An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta Molecular Cell Research. 2014; 1843(11):2528-2542. Pubmed PMID: 24983771; PMCID: PMC4158026.
Bertero T, Cottrill K, Krauszman A, Lu Y, Annis S, Hale A, Bhat B, Waxman AB, Chau BN, Kuebler WM, Chan SY (Senior Author). The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. Journal of Biological Chemistry. 2015; 290(4):2069-85. Pubmed PMID: 25505270; PMCID: PMC4303661.
White K, Lu Y, Annis S, Hale AE, Chau BN, Dahlman JE, Hemann C, Opotowsky AR, Vargas SO, Rosas I, Perrella MA, Osorio JC, Haley KJ, Graham BB, Kumar R, Saggar R, Saggar R, Wallace WD, Ross DJ, Khan OF, Bader A, Gochuico BR, Matar M, Polach K, Johannessen NM, Anderson DG, Langer R, Zweier JL, Bindoff LA, Systrom D, Waxman AB, Jin RC, Chan SY (Senior Author). Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Molecular Medicine. 2015; 7(6):695-713. Pubmed PMID: 25825391; PMCID: PMC4459813.
Closeup: Tang H, Ayon RJ, Yuan JX-Y. New insights into the pathology of pulmonary hypertension: implication of the miR-210/ISCU1/2/Fe-S axis. EMBO Molecular Medicine. 2015, 7(6):689-91. Pubmed PMID:25851536; PMCID: PMC4459811 (Commentary).
Parikh V, Park J, Nikolic I, Channick R, Yu PB, De Marco T, Hsue P*, Chan SY* (*Co-Senior Authors). Coordinated modulation of circulating miR-21 in HIV, HIV-associated pulmonary arterial hypertension, and HIV/HCV co-infection. Journal of Acquired Immune Deficiency Syndromes. 2015, 70(3): 236-241. Pubmed PMID: 26473639; PMCID: PMC4610144
Bertero T, Cottrill KA, Lu Y, Haeger CM, Dieffenbach P, Annis S, Hale A, Bhat B, Kaimal V, Zhang YY, Graham BB, Kumar R, Saggar R, Saggar R, Wallace WD, Ross DJ, Black SM, Fratz S, Fineman JR, Vargas SO, Haley KJ, Waxman AB, Chau BN, Fredenburgh LE, Chan SY (Senior Author). Matrix remodeling promotes pulmonary hypertension through feedback mechanoactivation of the YAP/TAZ-miR-130/301 circuit. Cell Reports. 2015, 13(5): 1016-32. Pubmed PMID: 26565914; PMCID: PMC4644508
Bertero T, Oldham WM, Cottrill KA, Pisano S, Vanderpool RR, Yu Q, Zhao J, Tai Y, Tang Y, Zhang YY, Rehman S, Sugahara M, Qi Z, Gorcsan III J, Vargas SO, Saggar R, Saggar R, Wallace WD, Ross DJ, Haley KJ, Waxman AB, Parikh VN, De Marco T, Hsue PY, Morris A, Simon MA, Norris KA, Gaggiol, C, Loscalzo J, Fessel J, Chan SY (Senior Author). Vascular stiffness mechanoactivates YAP/TAZ- dependent glutaminolysis to drive pulmonary hypertension. Journal of Clinical Investigation. 2016;126(9):3313-35. Pubmed PMID: 28548520; PMCID: PMC5004943.
Commentary: Bhattacharya, M. Stiff discipline for cells in pulmonary hypertension. Science Translational Medicine. 2016:358(8):358ec154. DOI: 10.1126/scitranslmed.aai8223.
Commentary: Dabral S, Pullamsetti, SS. Vascular stiffness and mechanotransduction: back in the limelight. American Journal of Respiratory and Critical Care Medicine. 2017;196(4):527-530. Pubmed PMID:28809511.