Imaging and Controlling Molecular Forces in Live Cell

我的研究项目旨在了解物理力量如何调节细胞行为。最近发现，机械力在生物系统的发展和功能中起着至关重要的作用。因此，了解和控制细胞微环境中的机械力为发现和生物技术发展提供了重要的机会。细胞与环境的相互作用主要通过黏附，细胞表面的黏附蛋白与环境中其他细胞或材料上的受体结合。细胞黏附研究的一个特别重要的领域是白细胞和循环肿瘤细胞的滚动黏附级联，这是炎症反应和癌症转移背后的关键过程。虽然现在可以很容易地在整个细胞尺度上测量力，但对分子水平上的粘附力的动力学知之甚少。理解和测量分子力是机械生物学面临的主要挑战之一。特别是，关于分子水平上的滚动附着力的大小、分布、化学计量、激活状态、信号传递和协同效应的定量知识很少。在分子水平上缺乏机制细节阻碍了在理解和控制细胞行为方面的进一步进展。我的研究计划旨在开发新的技术，在细胞黏附过程中可视化和控制单个黏附键上的力。应用我以前开发的力探针，我们将研究分子力事件在滚动粘附级联中的功能方面。应用DNA纳米技术，我们将继续推进和创造新的分子力探针来检测分子粘合事件的各个方面。了解分子力是如何影响细胞黏附和信号传递的，将在控制细胞行为方面开辟新的方向，超越传统的生化手段，使新的细胞筛选技术成为可能。由拟议的基础设施实现的研究将创造基础知识和应用技术，这些知识和应用技术可能使加拿大医疗保健系统、生物技术和制药行业受益。

My research program aims to understand how physical forces regulate cell behaviour. Mechanical forces were recently discovered to play a vital role in the development and functioning of biological systems. Therefore, understanding and controlling mechanical forces in the cellular micro-environment provides significant opportunities for discovery and biotechnology development. Cells interact with their environment mainly through adhesion, where adhesion proteins on cell surfaces bind to receptors on other cells or materials in the environment. A particularly important area of cell adhesion research is the rolling adhesion cascade of leukocytes and circulating tumor cells, which are key processes behind inflammatory response and cancer metastasis. Although forces can now be readily measured on the whole cell scales, very little is known about the dynamics of adhesion force at the molecular level. Understanding and measuring molecular forces is one of the major challenges facing mechano-biology. In particular, little quantitative knowledge exists on the rolling adhesion force magnitude, distribution, stoichiometry, activation state, signalling, and cooperative effects at the molecular level. The lack of mechanistic details at the molecular level hinders further advances in understanding and controlling of cell behaviours. My research program aims to develop new techniques to visualize and control forces across single adhesion bonds during cell adhesion. Applying force probes I have previously developed, we will investigate the functional aspects of molecular force events in rolling adhesion cascade. Applying DNA nanotechnology, we will continue to advance and create novel molecular force probes to detect various aspects of molecular adhesion events. Understanding how molecular forces influence cell adhesion and signalling will open new directions in controlling cell behaviour beyond conventional biochemical means, enabling novel cell screening technologies. Research enabled by the proposed infrastructure will create fundamental knowledge and applied technology that will potentially benefit the Canadian health care system, biotechnology, and pharmaceutical industries.