- Research program
Blood vessels play a prominent role in various human pathologies, including cancer, where the growth of new blood vessels facilitates continued tumour growth, and heart disease, where vascular inflammation drives vessel occlusion, resulting in heart attack and stroke. Our lab is motivated to understand the molecular control of endothelial cell function (the cells lining blood vessels) in both health and disease. We are especially interested in the molecular mechanisms that regulate endothelial gene expression at both the transcriptional and post-transcriptional levels. Our studies are uncovering novel roles for epigenetics (i.e. chromatin modifications) and noncoding RNAs (i.e. microRNAs and long noncoding RNAs) in these processes. Our studies are directly relevant to human disease, as an increased understanding of the molecular mechanisms governing blood vessel function is essential for innovation in therapies that modulate vascular growth or repress vascular inflammation.
- Approaches and current projects
We approach the study of endothelial cell biology from a multi-disciplinary approach. To gain insight into the mechanisms regulating vascular growth we employ developmental biology models, since the molecular pathways that control embryonic vascular differentiation and growth are often reutilized during postnatal vascular growth in disease processes or in tissue regeneration. Therefore, insight into these mechanisms from a developmental perspective will provide information that can be leveraged for the therapeutic regulation of postnatal vascular growth. Our research program utilizes several biological systems to identify the molecular cues (i.e. signaling and transcriptional pathways) that control vascular specification and growth, including embryonic stem (ES) cell differentiation models, zebrafish and mouse in vivo models and human primary endothelial cell in vitro models.
To gain insight into the pathways controlling vascular inflammation we primarily utilize mouse models of cardiovascular disease. We utilize cutting-edge technologies to probe the mechanisms of gene expression control, including genome-wide ChIP-sequencing approaches and various approaches to dissect the roles of noncoding RNA in the regulation of inflammatory signaling. Current projects include assessing the role of circulating microvesicles and the microRNAs that they contain in the regulation of vascular inflammation, and we are utilizing mouse models and human plasma samples to probe their function as well as their utility as biomarkers.
- 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)
Assistant 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