Fish Lab

Research Program

Blood vessels play a prominent role in various human pathologies, including cancer, where the growth of new blood vessels allows for continued tumour growth, and various retinopathies where uncontrolled pathological vascular growth precludes normal vision. On the other hand, new vessel growth is crucial for regenerative processes such as wound healing. Unfortunately, natural regenerative vascular growth is often insufficient to heal the catastrophic damage that occurs following a severe acute ischemic insult, such as a myocardial infarction. Increased understanding of the molecular mechanisms governing blood vessel development is crucial to innovation in therapies that either dampen pathological or promote physiological vascular growth. My research program is focused on determining the molecular mechanisms that direct the specification of endothelial cells that line blood vessels (vasculogenesis), and that control the formation and growth of new blood vessels (angiogenesis).

Approaches:

We approach this area of research from a developmental biology perspective since the molecular pathways that control embryonic vascular 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. Additionally, while a combination of vasculogenesis and angiogenesis establishes the vasculature during development, these two processes also occur in postnatal physiological or pathological vascular growth. For example, circulating endothelial progenitor cells can migrate to areas of ischemia and differentiate into endothelial cells through the process of vasculogenesis. Additionally, cell-based regenerative therapy will undoubtedly require an in-depth understanding of vascular differentiation.

My research program utilizes several biological systems to identify the molecular cues that control vascular specification and growth, including embryonic stem (ES) cell differentiation models, zebrafish in vivo models and human primary endothelial cell in vitro models.

Current projects

Several angiogenic signaling pathways converge to control the specification of endothelial cells and the growth of blood vessels. Currently, little is known about the complex regulatory networks downstream of angiogenic factor signaling, especially in regards to the establishment of endothelial-specific transcriptional programs. Considering the finely tuned response of vascular progenitors and endothelial cells to various growth factor gradients, it is also unclear what factors regulate the expression of cellular components of signaling transduction pathways. We have recently discovered that an endothelial-specific microRNA, miR-126, controls angiogenic signaling downstream of VEGF by negatively regulating inhibitors of signal transduction cascades (Fish et al, 2008), suggesting that post-transcriptional regulation can modulate the output of developmental signaling pathways.

Current projects are aimed at dissecting the complex regulatory networks that control endothelial specification and vascular growth, including chromatin-modulation by transcriptional pathways and post-transcriptional regulation of signal transduction pathways by microRNAs. This research program will provide new information regarding the mechanisms involved in this complex process, and will yield innovative therapeutic targets for diseases involving excess or insufficient vasculature.

Additional Appointments

Assistant Professor, Laboratory Medicine and Pathobiology

E-mail addresses:

Jason.fish@utoronto.ca

Selected Publications

Fish, J.E., Yan, M.S., Matouk, C.C., St. Bernard, R., Ho, J.J., Gavryushova, A., Srivastava, D. and Marsden, P.A. (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, J.E. and Srivastava, D. (2009). microRNAs: opening a new vein in angiogenesis research. Science Signaling 1(52): pe1.

Fish, J.E., Santoro, M.M., Morton, S.U., Yu, S., Yeh, R.F., Wythe, J.D., Ivey, K.I., Bruneau, B.G., Stainier, D.Y., 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, J.E., White, M.D., Yu, S., Smyth, J.W., Shaw, R.M., DiMaio, J.M. and Srivastava, D. (2008). Stromal cell-derived factor-1 alpha is cardioprotective after myocardial infarction. Circulation 117(17): 2224-2231.

Ivey, K.N., Muth, A., Arnold, J., King, F.W., Yeh, R.F., Fish, J.E., Hsiao, E.C., Schwartz, R.J., Conklin, B.R., Bernstein, H.S. 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)

Fish, J.E., Matouk, C.C.,Yeboah, E., Bevan, S.C.,Khan, M., Patil, K., Ohh, M, and Marsden, P.A. (2007). Hypoxia inducible expression of a natural cis-antisense transcript inhibits endothelial nitric-oxide synthase. Journal of Biological Chemistry 282(21): 15652-15666.

Fish, J.E, and Marsden, P.A. (2006). Endothelial nitric oxide synthase: insight into cell-specific gene regulation in the vascular endothelium. Cellular and Molecular Life Sciences 63(2): 144-62.

Fish, J.E., Matouk, C.C., Rachlis, C., Lin, S., Tai, S.C., D’Abreo, C. and Marsden, P.A. (2005). The expression of endothelial nitric oxide synthase is controlled by a cell-specific histone code. Journal of Biological Chemistry 280(26):24824-38

*Chan, Y., *Fish, J.E., D’Abreo, C., Lin, S., Robb, G.B., Teichert, A., Karantzoulis-Fegaras, F., Keightley, A., Steer, B.M. and Marsden P.A. (2004). The cell-specific expression of endothelial nitric oxide synthase: a role for DNA methylation. Journal of Biological Chemistry 279(33): 35087-35100. (*both authors contributed equally)