Biophysical Control of Cellular Programming and Tissue Patterning

细胞包含一个相当于30亿行指令代码的基因组，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，以形成复杂的形状。胚胎和肿瘤都使用相同的信息来实现截然不同的目的；然而，仅靠基因及其调控网络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血管、神经、肌肉、骨骼和结缔组织组成的节段性肢体和手指的细胞--就是精心策划了一组复杂而微妙的同时发生在细胞内和细胞内的事件。虽然被称为形态发生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，越来越明显的是，电信号也具有同样的重要性。事实上，除其他关键的发育过程外，去极化钙波被认为是启动增殖、迁移和凋亡的关键因素。生物电梯度调节组织边界、器官大小和身份。细胞生物电功能障碍--特别是静息膜电位(VMEM)--可能会促使细胞错误构型，从而导致出生缺陷和癌症。目前尚不清楚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来指导大规模的组织模式。我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。我设计了一个由NSERC Discovery Grant资助的为期5年的研究计划，短期目标是确定生物电控制的细胞机制和功能，这些细胞机制和功能驱动组织模式的三个基本特征：细胞命运、组织几何形状和微环境模式。我的跨学科方法将结合干细胞生物学、生物印刷、组织工程和生物电调制方面的尖端技术，将细胞命运和行为的电子语言转化为生物物理学的“Rosetta Stone”，对发育生物学、再生医学和生物医学工程具有变革性的影响。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写入细胞生物电码，以形成模式并控制组织生长。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极具市场价值的技能，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.