Stephen Y. Chan, MD, PhD, FAHA
Associate Professor of Medicine,
Associate Program Director -
BST 17th Floor
Assistant: Diane Margaria
Stephen Chan, MD, PhD, graduated from the Massachusetts Institute of Technology and received his MD and PhD from the University of California, San Francisco. He then completed an internship and residency in Internal Medicine at the Brigham and Women's Hospital (BWH) and fellowship training in Cardiology at the Massachusetts General Hospital. His postdoctoral research was performed in the laboratory of Joseph Loscalzo, MD, PhD, and Dr. Chan was faculty member at BWH and Harvard Medical School (2010-2015) where he was an Assistant Professor of Medicine. Dr. Chan recently accepted a position at the University of Pittsburgh Medical Center where he directs the Center for Pulmonary Vascular Biology and Medicine. He also serves as Associate Fellowship Director for Research in Cardiology.
Dr. Chan has held research grants from the National Institutes of Health, the American Heart Association, the Pulmonary Hypertension Association, and Gilead Sciences. He has been the recipient of philanthropic awards at BWH, including the Lerner Scholarship, the Watkins Discovery Award, the Harris Family Research Prize, and the McArthur-Radovsky Research Scholarship. Dr. Chan has been invited to present his research at both national and international venues, and he has received international research awards from the American College of Cardiology, the American Heart Association, and the American Society of Microbiology.
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.
Selected Publications and Annotations
STEPHEN Y. CHAN, Ying-Yi Zhang, Craig Hemann, Christopher E. Mahoney, Jay L. Zweier, Joseph Loscalzo. MicroRNA-210 controls mitochondrial metabolism during hypoxia by repressing the iron-sulfur cluster assembly proteins ISCU1/2. Cell Metabolism. 2009; 10 (4); 273 – 284.
Repression of mitochondrial respiration represents an evolutionarily ancient cellular adaptation to hypoxia, but its underlying molecular mechanisms are incompletely understood. This study identified the hypoxia-induced microRNA-210 as an essential regulator of the metabolic processes that govern this “Pasteur effect,” via repression of its direct target, the iron-sulfur cluster assembly proteins ISCU1/2 thus leading to a metabolic shift from mitochondrial oxidative phosphorylation to glycolysis. Taken together, these results identified important mechanistic connections among microRNAs, iron-sulfur cluster biology, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to stress.
Aaron L. Baggish, Andrew Hale, Rory B. Weiner, Gregory D. Lewis, David Systrom, Francis Wang, Thomas J. Wang, STEPHEN Y. CHAN. Dynamic regulation of circulating microRNA during acute exhaustive exercise and sustained aerobic exercise training. Journal of Physiology. 589:3983-3994 (2011).
Victoria N. Parikh, Richard C. Jin, Sabrina Rabello, Natali Gulbahce, Kevin White, Andrew Hale, Katherine A. Cottrill, Rahamthulla S. Shaik, Aaron B. Waxman, Ying-Yi Zhang, Bradley A. Maron, Jochen C. Hartner, Yuko Fujiwara, Stuart H. Orkin, Kathleen J. Haley, Albert-László Barabási, Joseph Loscalzo, STEPHEN Y. CHAN. MicroRNA-21 integrates pathogenic signaling to control pulmonary hypertension: results of a network bioinformatics approach. Circulation. 125:1520-1532 (2012).
Jonathan W. Snow, Andrew Hale, Stephanie K. Isaacs, Aaron L. Baggish, STEPHEN Y. CHAN. Ineffective delivery of diet-derived microRNAs to recipient animal organisms. RNA Biology. 10: 1107-1116 (2013).
Aaron L. Baggish, Joseph Park, Pil-Ki Min, Stephanie K. Isaacs, Beth A. Parker, Paul D. Thompson, Christopher Troyanos, Pierre D’Hemecourt, Sophia Dyer, Marissa Thiel, Andrew Hale, STEPHEN Y. CHAN. Rapid up-regulation and clearance of distinct circulating microRNAs after prolonged aerobic exercise. Journal of Applied Physiology. 116: 522-531 (2014).
Thomas Bertero, Yu Lu, Sofia Annis, Andrew Hale, Balkrishen Bhat, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Sara O. Vargas, Brian B. Graham, Rahul Kumar, Stephen M. Black, Sohrab Fratz, Jeffrey R. Fineman, James D. West, Kathleen J. Haley, Aaron B. Waxman, B. Nelson Chau, Katherine A. Cottrill, STEPHEN Y. CHAN. Systems-level regulation of microRNA networks by miR-130/301 promotes pulmonary hypertension. The Journal of Clinical Investigation. 124:3514-3528 (2014).
Andrew Hale, Changjin Lee, Sofia Annis, Pil-Ki Min, Reena Pande, Mark A. Creager, Colleen G. Julian, Lorna G. Moore, S. Alex Mitsialis, Sarah J. Hwang, Stella Kourembanas, STEPHEN Y. CHAN. An Argonaute 2 switch regulates circulating miR-210 to coordinate hypoxic adaptation across cells. Biochim Biophys Acta Molecular Cell Research. 1843:2528-2542 (2014).
Thomas Bertero, Katherine Cottrill, Adrienn Krauszman, Yu Lu, Sofia Annis, Andrew Hale, Balkrishen Bhat, Aaron B. Waxman, B. Nelson Chau, Wolfgang M. Kuebler, STEPHEN Y. CHAN. The microRNA-130/301 family controls vasoconstriction in pulmonary hypertension. Journal of Biological Chemistry. 290:2069-2085 (2015).
Kevin White, Yu Lu, Sofia Annis, Andrew E. Hale, B. Nelson Chau, James E. Dahlman, Craig Hemann, Alexander Opotowsky, Sara O. Vargas, Rosas I, Mark A. Perrella, Juan C. Osorio, Kathleen J. Haley, Brian B. Graham, Rahul Kumar, Rajan Saggar, Rajeev Saggar, W. Dean Wallace, David J. Ross, Omar F. Khan, Andrew Bader, Bernadette R. Gochuico, Majed Matar, Kevin Polach, Nicolai M. Johannessen, Daniel G. Anderson, Robert Langer, Jay L. Zweier, Laurence A. Bindoff, David Systrom, Aaron B. Waxman, Richard C. Jin, STEPHEN Y. CHAN. Genetic and hypoxic alterations of the microRNA-210-ISCU1/2 axis promote iron-sulfur deficiency and pulmonary hypertension. EMBO Molecular Medicine. 7:695-713 (2015).
Victoria Parikh, Joseph Park, Ivana Nikolic, Richard Channick, Paul B. Yu, Teresa De Marco, Priscilla Hsue, STEPHEN Y. CHAN. Coordinated modulation of circulating miR-21 in HIV, HIV-associated pulmonary arterial hypertension, and HIV/HCV co-infection. Journal of Acquired Immune Deficiency Syndromes. In press (2015).
A unique network biology–based approach was coupled with experimental validation in vitro and in vivo to identify microRNA-21 (miR-21) as a crucial pathogenic regulator in pulmonary hypertension (PH). This study was the first to demonstrate the utility of a network-based method for identifying disease modifying miRNAs.
Guided by in silico network analysis and in vivo experimentation, this was the first description of any microRNA family, miR-130/301, regulating a hierarchy of subordinate microRNAs with global yet cell type-specific effects in PH. It defined the systems-level regulation of microRNA/gene networks in PH with broad implications on microRNA-based therapeutics.
This study identified the miR-210-ISCU1/2 axis as a pathogenic lynchpin causing iron-sulfur (Fe-S) deficiency and pulmonary hypertension (PH). It was first to report pulmonary vascular dysfunction in ISCU-deficient individuals. These findings have spurred development of diagnostics and therapeutics targeting Fe-S biogenesis in PH and diseases that share similar metabolic underpinnings.