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

在心血管发育过程中，心脏及其流出道来源于胚胎内的前体细胞。我的实验室对这些前体细胞如何成为心脏的心肌细胞和流出道的血管平滑肌细胞（VSMCs）特别感兴趣。这种特化的过程被称为分化，调控心脏和流出道分化的分子机制仍不完全清楚。分化过程在一定程度上与程序性细胞死亡相反，程序性细胞死亡是一个术语，用于描述不再需要的细胞的移除。这个过程是由Bcl-2蛋白家族调控的。我实验室的数据显示，在心脏和VSMC分化中起关键作用的心肌素可以通过microrna的表达影响心肌细胞分化和对抗细胞死亡，从而抑制促死亡的Bcl-2家族成员，称为Bnip3和Bnip3（即Nix）。

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.