Modulation of cell death and differentiation by myocardin-regulated microRNAs during mammalian development

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During cardiovascular development, the heart and its outflow tract are derived from precursor cells that reside within the embryo. My laboratory is particularly interested in how these precursor cells can become cardiac myocytes of the heart and vascular smooth muscle cells (VSMCs) of the outflow tract. This process of specialization is called differentiation and the molecular mechanisms that regulate differentiation in the heart and outflow tract remain incompletely understood. The process of differentiation is partly opposed by programmed cell death, which is a term used to describe the removal of cells that are no longer necessary. This process is regulated by the Bcl-2 family of proteins. Data from my laboratory has shown that myocardin, which has a critical role in cardiac and VSMC differentiation, can affect both myocyte differentiation and oppose cell death through the expression of microRNAs, which in turn inhibit the pro-death Bcl-2 family members, called Bnip3 and Bnip3L (i.e. Nix). Cell death and differentiation of cardiac and vascular smooth muscle cells is the central focus of my research program. In the next 5-year cycle, my group will determine how myocardin regulates cell death and differentiation, and how Bnip3 and Nix are regulated by signaling pathways. My HQP use innovative and mechanistic cell and molecular biology techniques, including human induced pluripotent stem cells (iPSCs) that can be differentiated into cardiomyocytes and VSMCs using commercially available media. In addition, we use primary rodent cardiomyocytes and vascular smooth muscle cells, and immortalized cells lines to work out the molecular details of our experiments and develop more advanced cell culture skills of trainees working in my laboratory. I predict that 3 PhD students and 3 MSc students will graduate from my lab over the next 5-years. The scientific community's keen interest in stem cell biology strongly suggests that knowledge regarding the mechanisms by which cardiac and VSMCs differentiate from precursor cells will be sought after by cardiovascular physiologists and developmental biologists investigating more applied aspects of this field. Furthermore, my laboratory has considerable experience dissecting the control processes that regulate cell death and differentiation, while maintaining a strong commitment to graduate student training. Collectively, this proposed program of research is feasible, significant, and consistent with the mandate of NSERC.