Biophysical Control of Cellular Programming and Tissue Patterning

细胞包含的基因组相当于30亿行指令代码，存储的信息指导从蛋白质合成到其他细胞之间的远程通信，形成复杂的形状。胚胎和肿瘤都利用同样的信息来达到截然不同的目的；然而，基因及其调控网络本身并不能解释数百万甚至数十亿细胞是如何协调在有图案的组织中实现功能性多细胞的。从单个细胞构建一个完整的有机体——一个表达由相互交织的脉管系统、神经、肌肉、骨骼和结缔组织组成的四肢和手指的细胞——是一套深不可测的复杂而微妙的同时发生的细胞间和细胞内事件。虽然很明显，被称为形态发生因子的特殊生物分子对形态的获得（形态发生）是不可或缺的，但近年来，电信号的重要性越来越明显。事实上，已知去极化钙波可以启动增殖、迁移和凋亡等关键发育过程。生物电梯度调节组织边界、器官大小和身份。细胞生物电的功能障碍——特别是静息膜电位（Vmem）——可以促使细胞的错误模式，从而诱发出生缺陷和癌症。目前尚不清楚的是Vmem的时空模式对独立指定细胞命运的贡献，以及这些动态如何与遗传，生化和微环境因素相互作用以指导大规模组织模式。我的研究计划的长期目标是解决这一知识差距，并揭示生物电在组织模式中的互补作用，我设计了一个为期5年的NSERC发现资助的研究计划，其短期目标是确定驱动组织模式的三个基本特征的生物电控制的细胞机制和功能：细胞命运，组织几何和微环境模式。我的跨学科方法将结合干细胞生物学、生物打印、组织工程和生物电调制的尖端技术，翻译细胞命运和行为的电子语言，一个生物物理学的“罗塞塔石碑”，对发育生物学、再生医学和生物医学工程具有变革意义。拟议的研究计划将对生物学领域产生重大影响，使研究人员能够读取和编写细胞生物电密码，以模式和控制组织生长。我的HQP团队将受益于世界级的指导，并在生物医学工程和干细胞生物学方面获得高度市场化的技能，这将使他们成为下一代领先的国际学术和行业科学家的一部分。

Cells contain a genome equivalent to 3 billion lines of instructional code, storing information that directs everything from protein synthesis to long-range communication amongst other cells to form complex shape. Both embryos and tumors use this same information to achieve very different ends; however, genes and their regulatory networks alone, do not explain how millions, or even billions of cells coordinate to achieve functional multicellularity within patterned tissues. To construct an entire organism from a single cell - one that expresses segmented limbs and digits comprised of interwoven vasculature, nerve, muscle, bone, and connective tissue - is to orchestrate an unfathomably complex yet delicate set of simultaneous inter- and intra-cellular events. While it is clear that specialized biomolecules called morphogens are integral to the acquisition of form (morphogenesis), in recent years it has become increasingly evident that electrical signals are of equal importance. Indeed, depolarizing calcium waves are known to initiate proliferation, migration, and apoptosis among other key developmental processes. And bioelectric gradients regulate tissue boundaries, organ size, and identity. Dysfunctions of cellular bioelectricity - particularly, resting membrane potential (Vmem) - can prompt mispatterning of cells to induce birth defects and cancers. What remains unknown is the contribution of spatio-temporal patterns of Vmem to specifying cell fate independently and how these dynamics interplay with genetic, biochemical and microenvironmental factors to direct large-scale tissue patterning. My long-term goal of my research program is to address this knowledge gap and reveal the complementary role of bioelectricity in tissue patterning, I have designed a 5-year NSERC Discovery Grant funded research program with short-term objectives to determine cell mechanisms and functions of bioelectric control that drive three fundamental features of tissue patterning: cell fate, tissue geometry, and microenvironment patterning. My interdisciplinary approach will combine cutting-edge techniques in stem cell biology, bioprinting, tissue engineering, and bioelectric modulation to translate the electrical language of cell fate and behaviour, a biophysical `Rosetta Stone', with transformative implications for developmental biology, regenerative medicine, and biomedical engineering. The proposed research program will significantly impact the field of biology, allowing researchers to read and write cellular bioelectric codes to pattern and control tissue growth. My team of HQP will benefit from world-class mentorship and acquire highly marketable skills in biomedical engineering and stem cell biology that will allow them to be a part of the next generation of leading international academic and industry scientists.