Education
- BS - 1995, Massachusetts Institute of Technology
- MD, PhD (MSTP) - 2003, University of California, San Francisco
Research Interests
Dr. Chan directs a research program and clinical center investigating mechanisms of pulmonary hypertension (PH), the systems biology of endothelial function, and heart-lung-brain axis communication in health and disease.
Career focus on pulmonary hypertension, systems biology, and the heart-lung-brain axis: I am a physician-scientist and cardiologist and serve as Director of the Vascular Medicine Institute (VMI). I also direct a research program and clinical center investigating mechanisms of pulmonary hypertension (PH), the systems biology of endothelial function, and heart-lung-brain axis communication in health and disease. At a translational level, PH is a vascular disease with enigmatic origins, increasing global significance, and unmet needs. Defining the complex molecular controls of PH and its systemic manifestations are crucial for designing a cure.
We seek to merge population-level molecular epidemiology with experimental biology and bioengineering to translate fundamental discoveries to clinical paradigm advances. Our program combines molecular and clinical molecular bioinformatics with unique rodent, human, and bioengineered vascular platforms to accelerate systems-wide discovery in vascular disease. My lab has defined genetic and acquired mechanisms of altered metabolism in PH, identifying iron-sulfur deficiencies and glutaminolysis as key disease drivers. This work serves as a basis for glutamine restriction as a dietary therapy for PH; clinical development of 18F-glutamine tracer for positron emission tomography (PET) diagnostic imaging; and testing therapeutic glutaminase inhibitors in humans. We have also identified regulatory processes of inflammation and mechanosensing in PH. We were the first to demonstrate the systems-level importance of non-coding RNAs in PH. More recently, we established a genetic and metabolic paradigm that links lysosomal biology and oxysterol generation to endothelial inflammation and PH. In doing so, we are defining metabolomic signatures identifying persons at-risk for PH mortality and developed new lysosomal therapies for vascular disease.
Selected Publications
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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 Metab. 2009; 10 (4); 273-284. PMCID: PMC2759401.
This study defined the mechanistic connections among microRNAs, hypoxia, and mitochondrial function, with broad implications for cellular metabolism and adaptation to stress.
2. 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.
This was the first report to define the dynamic regulation of circulating microRNAs with aerobic exercise and their possible roles as physiological mediators of exercise-induced cardiovascular adaptation.
3. 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. PMCID: PMC3353408.
Using pulmonary hypertension as a discovery platform, this study was the first to describe in silico network-based methodology for identifying disease-modifying microRNAs in vivo.
4. 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, Gaggioli C, Loscalzo J, Fessel J, Chan SY (Senior Author). Vascular stiffness mechanoactivates YAP/TAZ-dependent glutaminolysis to drive pulmonary hypertension. J Clin Invest. 2016;126(9):3313-3335. PMCID: PMC5004943.
This study demonstrated that vessel stiffness mechanoactivates glutaminolysis to induce proliferation in pulmonary hypertension, establishing the paradigm connecting matrix stiffening to glutamine metabolism.
5. Yu Q, Tai YY, Tang Y, Zhao J, Negi V, Culley MK, Pilli J, Sun W, Brugger K, Mayr J, Saggar R, Saggar R, Wallace WD, Ross DJ, Waxman AB, Wendell SG, Mullett SJ, Sembrat J, Rojas M, Khan OF, Dahlman J, Sugahara M, Kagiyama N, Satoh T, Zhang M, Feng N, Gorcsan J, Vargas SO, Haley KJ, Kumar R, Graham BB, Langer R, Anderson DG, Wang B, Shiva S, Bertero T, Chan SY (Senior Author). BOLA3 deficiency controls endothelial metabolism and glycine homeostasis in pulmonary hypertension. Circulation. 2019. 139:2238-2255. PMCID: PMC6519484.
This work identified BOLA3 as a crucial lynchpin connecting oxidative metabolism and glycine homeostasis with endothelial dysfunction in PH, thus providing a molecular explanation for the clinical associations linking PH with hyperglycinemic syndromes and mitochondrial disorders.
6. Negi V, Yang J, Speyer G, Pulgarin A, Handen A, Zhao J, Tai YY, Tang Y, Culley MK, Yu Q, Forsythe P, Gorelova A, Watson AM, Al Aaraj Y, Satoh T, Sharifi-Sanjani M, Rajaratnam A, Sembrat J, Provencher S, Yin X, Vargas SO, Rojas M, Bonnet S, Torrino S, Wagner BK, Schreiber SL, Dai M, Bertero T, Al Ghouleh I, Kim S, Chan SY (Senior Author). Computational repurposing of therapeutic small molecules from cancer to pulmonary hypertension. Sci Adv. 2021; 7(43):eabh3794. Epub 2021 Oct 20. PMCID: PMC8528428.
In this study, a network dependency platform was generated to computationally predict and experimentally define a landscape of cancer drug mechanisms in pulmonary hypertension.
7. Culley MK, Zhao J, Tai YY, Tang Y, Perk D, Negi V, Yu Q, Woodcock C-SC, Handen A, Speyer G, Kim S, Lai Y-C, Satoh T, Watson A, Al Aaraj Y, Sembrat J, Rojas M, Goncharov D, Goncharova EA, Khan OF, Anderson DG, Dahlman JE, Gurkar A, Lafyatis R, Fayyaz AU, Redfield MM, Gladwin MT, Rabinovitch M, Gu M, Bertero T, Chan SY (Senior Author). Frataxin deficiency promotes endothelial senescence in pulmonary hypertension. J Clin Invest. 2021; 131:e136459. PMCID: PMC8159699.
This work established an endothelial etiology for PH in Friedreich’s ataxia and left heart disease, supporting therapeutic development of senolytic drugs to reverse effects of iron-sulfur deficiency across PH subtypes.
8. Rachedi NS, Tang Y, Tai YY, Zhao J, Chauvet C, Grynblat J, Akoumia KF, Estephan L, Torrino S, Sbai C, Ait-Mouffok A, Latoche JD, Al Aaraj Y, Brau F, Abélanet S, Clavel S, Zhang Y, Guillermier C, Kumar NVG, Tavakoli S, Mercier O, Risbano MG, Yao Z-K, Yang G, Ouerfelli O, Lewis JS, Montani D, Humbert M, Steinhauser ML, Anderson C, Oldham WM, Perros F, Bertero T*, Chan SY* (*Co-Senior Authors). Dietary intake and glutamine-serine metabolism control pathologic vascular stiffness. Cell Metab. 2024; 36(6): 1335-1350. PMID: 38701775. PMCID: PMC11152997.
This study defined the specific metabolic pathways crucial for vascular collagen biosynthesis, providing guidance for incorporating metabolic and dietary interventions for treating cardiopulmonary vascular disease.
9. Tai Y-Y, Yu Q, Tang Y, Sun W, Kelly NJ, Okawa S, Zhao J, Schwantes-An T-H, Lacoux C, Torrino S, Al Aaraj Y, El Khoury W, Negi V, Liu M, Corey CG, Belmonte F, Vargas SO, Schwartz B, Bhat B, Chau BN, Karnes JH, Satoh T, Barndt RJ, Wu H, Parikh VN, Wang J, Zhang Y, McNamara D, Li G, Speyer G, Wang B, Shiva S, Kaufman B, Kim S, Gomez D, Mari B, Cho MH, Bouiez A, Pauciulo MW, Southgate L, Trembath RC, Sitbon O, Humbert M, Graf S, Morrell NW, Rhodes CJ, Wilkins MR, Nouraie M, Nichols WC, Desai AA, Bertero T, Chan SY (Senior Author). Allele-specific control of rodent and human lncRNA KMT2E-AS1 promotes hypoxic endothelial pathology in pulmonary hypertension. Sci Transl Med. 2024. 16(729): eadd2029. DOI: 10.1126/scitranslmed.add2029. PMID: 38198571; PMCID: PMC10947529.
This study identified the integrated epigenetic, metabolic, and RNA-based paradigms that control hypoxia-dependent physiology and endothelial reprogramming in pulmonary hypertension.
10. Harvey LD, Alotaibi M, Tai YY, Tang Y, Kim HJ, Kelly NJ, Sun W, Woodcock CC, Arshad S, Culley MK, El Khoury W, Xie R, Al Aaraj Y, Zhao J, Hafeez N, Rao RJ, Jiang S, Negi V, Kirillova A, Perk D, Watson AM, St. Croix CM, Stolz DB, Lee JY, Cheng MH, Zhang M, Detmer S, Guzman E, Manan R, Saggar R, Haley KJ, Waxman AB, Okawa S, Schwantes-An TH, Pauciulo MW, Wang B, Webb A, Chauvet C, Anderson DG, Nichols WC, Desai AA, Lafyatis R, Nouraie M, Wu H, McDonald JG, Cheng S, Bahar I, Bertero T, Benza RL, Jain M, Chan SY (Senior Author). Lysosomal dysfunction and inflammatory sterol metabolism in pulmonary arterial hypertension. Science. 2025; 387(6732): eadn7277. PMID: 39847635. PMC: PMC12087357.
Using multi-dimensional analyses across genomic and metabolomic datasets in combination with experimental validation, this study established a genetic and metabolic paradigm that links lysosomal biology and oxysterol and bile acid processes to EC inflammation and pulmonary hypertension, thus carrying implications for diagnostic and therapeutic development.