BBS Faculty Member - Stephen Chan

Stephen Chan

Department of Medicine

Brigham and Women's Hospital
New Research Building, Room 630N
77 Avenue Louis Pasteur
Boston, MA 02115
Tel: 617-525-4844
Fax: 617-525-4830
Email: sychan@partners.org
Visit my lab page here.



Complex human diseases are nearly always triggered by factors functioning in an interconnected network that traditional reductionistic methods fail to recognize. To capitalize on the emerging discipline of "network medicine," research in the Chan laboratory utilizes a combination of network-based bioinformatics with unique experimental reagents derived from genetically altered rodents as well as human subjects to accelerate systems-wide discovery in cardiopulmonary vascular disease.

We study pulmonary hypertension (PH) as a prototypical example of an enigmatic human disease where reductionistic studies have primarily focused on end-stage molecular effectors. Clinically, PH is an increasingly prevalent and at times fatal condition characterized by elevated pulmonary arterial pressures and right ventricular failure. Etiologies are diverse and include exposure to low oxygen (
e.g., hypoxia), inflammation, and high-flow states, among many others. Ironically, study of PH-relevant molecular effectors in isolation without considering their functional interconnections has worsened the confusion surrounding their dynamic roles in pathogenesis.

Our published work has identified the crucial importance of microRNA (miRNA), which are small, non-coding RNA that negatively regulate gene expression, in processes critical to PH progression, including metabolic adaptation to hypoxia (1) and exercise (2). Currently, there is a growing appreciation that a single or multiple miRNA can regulate related disease targets in a cooperative fashion. Accordingly, we have developed and validated a novel network-based approach (3) to rank miRNA as the most robust regulators of PH by their predicted recognition of multiple targets in the same functional network of PH-associated genes. This study introduces the utility of a network-based method for discerning the behavior of molecular networks of miRNA and their targets in coordinately controlling disease (4).

Consequently, ongoing projects focus on the prediction and confirmation of how networks of miRNA and other small molecules concertedly regulate target gene networks, thus impacting intermediate phenotypes (
e.g., metabolism) and consequent vascular phenotypes in vivo. In doing so, we aim to prove that combining network theory with experimental validation can substantially 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.



Last Update: 7/10/2014



Publications

For a complete listing of publications click here.

 


 

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.

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.

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.

Snow JW, Hale A, Isaacs SK, Baggish AL, Chan SY (Senior Author). Ineffective Delivery of Diet-Derived MicroRNAs to Recipient Animal Organisms. RNA Biology. 2013; 10(7): 1107-16.

Baggish AL, Park J, Min PK, Isaacs S, Parker BA, Thompson PD, Troyanos C, D’Hemecourt P, Dyer S, Thiel M, Hale A, Chan SY (Senior Author). Rapid Up-Regulation and Clearance of Distinct Circulating MicroRNAs After Prolonged Aerobic Exercise. Journal of Applied Physiology. 2014; 116(5): 522-531.

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. The Journal of Clinical Investigation. 2014; Epublication ahead of print.

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 Mol Cell Res. 2014; Epublication ahead of print.



© 2013 by the President and Fellows of Harvard College