Research Overview:

Endothelial cells are dynamic integrators of their microenvironment, translating physiological and pathological cues into coordinated biological responses. As key regulators of vascular function, they play central roles in both health and disease.

The Fish Lab investigates the molecular mechanisms that govern endothelial cell biology across a spectrum of vascular and cardiometabolic diseases. We discovered that somatic KRAS mutations within the endothelium are the primary cause of sporadic brain arteriovenous malformations (bAVMs). Building on this finding, we developed preclinical models of bAVM and leverage human patient-derived samples, including organoid systems and high-throughput screening platforms, to identify and test novel therapeutic strategies.

Our research also examines how systemic inflammation and endothelial activation may create a susceptibility to cardiac damage during chemotherapy. We study how tumours influence the cardiac vasculature, how endothelial cells respond to chemotherapeutic agents, and how they communicate with cardiomyocytes through extracellular vesicles. In other projects in the lab, we investigate how diabetes alters cardiac microvascular function and how heart failure affects the brain, with the goal of defining vascular mechanisms that link multi-organ disease.

We employ a multidisciplinary and translational approach that integrates zebrafish and mouse models of cardiovascular disease, cultured human endothelial cells, organoid systems, and analysis of human clinical specimens. The Fish lab is a vibrant training environment where intellectual curiosity, scientific rigor, and team science are valued. Close collaboration with clinician-scientists enables us to move discoveries from bench to bedside.

Our experimental toolkit includes functional interrogation of signaling and gene regulatory pathways, genome-wide approaches to define transcriptional networks, CRISPR-based genome engineering, high-throughput screening, and mechanistic studies of extracellular vesicle-mediated communication.

Dr. Jason Fish completed his PhD at the University of Toronto in the laboratory of Dr. Philip Marsden in 2006. Here he uncovered a role for epigenetics in gene regulation in blood vessels. This was followed by postdoctoral training in the laboratory of Dr. Deepak Srivastava at the Gladstone Institute of Cardiovascular Disease and the University of California, San Francisco. Here, Dr. Fish uncovered a role for microRNAs in regulating the development of the cardiovascular system. Dr. Fish returned to Toronto in 2010. He is currently a Senior Scientist at the Peter Munk Cardiac Centre, UHN Research Institutes and a Full Professor in the Department of Laboratory Medicine and Pathobiology. Dr. Fish previously held the Canada Research Chair in Vascular Cell and Molecular Biology and is the past-president of the North American Vascular Biology Organization.

For a list of Dr. Fish's publications, please visit PubMed, Scopus or ORCID.

Selected Publications

• Cheng HS, Njock MS, Khyzha N, Dang LT and Fish JE. (2014). Noncoding RNAs regulate NF-kappaB signaling to modulate blood vessel inflammation. Frontiers in Genetics. Dec 10, E-Pub ahead of print.
• Delgado-Olguin P, Dang LT, He D, Thomas S, Chi L, Sukovic T, Khyzha N, Dobenecher MW, Fish JE, Bruneau BG. (2014). Ezh2-mediated repression of a transcriptional pathway upstream of Mmp9 maintains integrity of the developing vasculature. Development 141(23):4610-7.
• Wythe JD, Dang LT, Devine WP, Boudreau E, Artap ST, He D, Schachterle W, Stainier DY, Oettgen P, Black BL, Bruneau BG, Fish JE. (2013). ETS factors regulate Vegf-dependent arterial specification. Developmental Cell 15;26(1):45-58.
• Cheng HS, Sivachandran N, Lau A, Boudreau E, Zhao JL, Baltimore D, Delgado-Olguin P, Cybulsky MI, Fish JE. (2013). MicroRNA-146 represses endothelial activation by inhibiting pro-inflammatory pathways. EMBO Molecular Medicine 5(7):949-66.
• Dang LT, Lawson ND, Fish JE. (2013). MicroRNA control of vascular endothelial growth factor signaling output during vascular development. Arteriosclerosis Thrombosis and Vascular Biology 33(2):193-200.
• Fish JE, Cybulsky MI. (2012). Taming endothelial activation with a microRNA. Journal of Clinical Investigation 1;122(6):1967-70.
• Fish JE, Wythe JD, Xiao T, Bruneau BG, Srivastava D, Woo S. (2011). A Slit/miR-218/Robo regulatory loop is required during heart tube formation in zebrafish. Development 138(7):1409-19.
• Fish JE, Yan MS, Matouk CC, St. Bernard R, Ho JJ, Gavryushova A, Srivastava D and Marsden PA. (2010). Hypoxic repression of endothelial nitric oxide synthase transcription is coupled with eviction of promoter histones. Journal of Biological Chemistry 285(2):810-26. (Featured as Paper of the Week and in a Podcast Interview)
• Fish JE and Srivastava D. (2009). microRNAs: opening a new vein in angiogenesis research. Science Signaling 1(52): pe1.
• Fish JE, Santoro MM, Morton SU, Yu S, Yeh RF, Wythe JD, Ivey KI, Bruneau BG, Stainier DY and Srivastava D. (2008). miR-126 regulates angiogenic signaling and vascular integrity. Developmental Cell 15(2): 272-284. (Featured on the cover)
• Saxena A, Fish JE, White MD, Yu S, Smyth JW, Shaw RM, DiMaio JM and Srivastava D. (2008). Stromal cell-derived factor-1 alpha is cardioprotective after myocardial infarction. Circulation 117(17): 2224-2231.
• Ivey KN, Muth A, Arnold J, King FW, Yeh RF, Fish JE, Hsiao EC, Schwartz RJ, Conklin BR, Bernstein HS and Srivastava D. (2008). MicroRNA regulation of cell lineages in mouse and human embryonic stem cells. Cell Stem Cell 2(3): 219-229. (Featured on the cover)

• Professor, Department of Laboratory Medicine and Pathobiology, University of Toronto
• Member, Heart and Stroke Richard Lewar Centre of Excellence
• Tier 2 Canada Research Chair in Vascular Cell and Molecular Biology

Canada Research Chair in Vascular Cell and Molecular Biology