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

哺乳动物发育过程中心肌素调节的 microRNA 对细胞死亡和分化的调节

• 批准号: RGPIN-2019-05409
• 负责人: Gordon, Joseph
• 金额: $ 2.33万
• 依托单位: University of Manitoba
• 依托单位国家: 加拿大
• 项目类别: Discovery Grants Program - Individual
• 财政年份: 2021
• 资助国家: 加拿大
• 起止时间: 2021-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://www.nserc-crsng.gc.ca/ase-oro/Details-Detailles_eng.asp?id=738256
• 关键词: Modulation; cell; death; differentiation; myocardin

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.

在心血管发育过程中，心脏及其流出道来自胚胎内的前体细胞。我的实验室特别感兴趣的是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)。这种特化的过程被称为分化，调节心脏和流出道分化的分子机制仍然不完全清楚。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用来描述不再需要的细胞被移除的术语。这一过程受Bcl2蛋白家族的调控。来自我的实验室的数据表明，在心脏和VSMC分化中起关键作用的myocardin可以影响心肌细胞的分化，并通过表达microRNAs来对抗细胞死亡，而microRNAs反过来又抑制了促死亡的Bcl-2家族成员Bnip3和Bnip3L(即Nix)。心脏和血管平滑肌细胞的细胞死亡和分化是我的研究项目的中心焦点。在接下来的五年周期中，我的团队将确定myocardin如何调节细胞死亡和分化，以及Bnip3和Nix如何通过信号通路调节。My HQP使用创新和机械的细胞和分子生物学技术，包括人类诱导的多能干细胞(IPSCs)，可以使用商业上可用的培养液分化为心肌细胞和VSMC。此外，我们使用原代啮齿动物心肌细胞和血管平滑肌细胞，以及永生化细胞系来确定我们实验的分子细节，并为在我的实验室工作的受训人员开发更先进的细胞培养技能。我预计未来5年将有3名博士生和3名硕士研究生从我的实验室毕业。科学界对干细胞生物学的浓厚兴趣强烈表明，心血管生理学家和发育生物学家将寻求关于心脏和血管平滑肌细胞与前体细胞分化机制的知识，研究这一领域的更多应用方面。此外，我的实验室在剖析调控细胞死亡和分化的控制过程方面有相当多的经验，同时保持了对研究生培训的坚定承诺。总体而言，这项拟议的研究计划是可行的、有意义的，并与NSERC的任务一致。