Using video force microscopy (VFM) to determine the forces that drive morphogenetic movements of cells and tissues

大多数人没有意识到细胞和组织运动对人类健康有多么重要。然而，正是通过这样的运动，器官和其他关键结构在早期胚胎发育期间形成，伤口愈合，细胞离开原发癌症肿瘤并建立转移，适当的结构和功能在工程组织中产生。这些运动是由亚细胞结构成分驱动的，它们所产生的力量的变化可以显著影响健康结果。人们可以设想药物和其他手段来治疗操纵这些力量，但如果我们要评估拟议的干预措施，我们必须有实用的方法来衡量它们，这就是我的研究计划的目标。 我的研究团队最近发明了一种方法，可以根据细胞和组织运动的时间推移电影来确定它们的作用力。当这种名为视频力显微镜(VFM)的新计算建模技术被用于研究果蝇(果蝇)胚胎腹侧沟的形成时，它使得绘制作用于单个细胞的力并跟踪这些力如何随时间变化成为可能。这一新知识解释了为什么有些胚胎发育正常，而另一些胚胎则有先天缺陷。 发现基金是必要的，这样我的团队才能解决数学和机械问题，这些问题限制了这项前景光明的技术的可靠性和普遍适用性。例如，如果单层薄片中的单元同时受到沿其边缘和顶面收缩的驱动，我们当前的VFM算法可能难以区分每个单元的贡献。我们希望解决这些问题，并使用VFM来研究伤口愈合和其他重要的细胞和组织运动。我们希望VFM将成为研究细胞和组织力学的标准工具，我们希望它将导致改进预防出生缺陷和癌症转移的策略，并在组织工程中产生新的方法。

Most people do not realize how important cell and tissue movements are to human health. However, it is through such movements that organs and other critical structures form during early embryo development, that wounds heal, that cells leave a primary cancer tumour and establish metastases, and that proper structure and function arise in engineered tissues. These movements are driven by sub-cellular structural components, and alterations to the forces they generate can significantly impact health outcomes. One could conceive pharmaceutical and other means to therapeutically manipulate these forces, but we must have practical ways to measure them if we are to evaluate proposed interventions, and that is the goal of my research program. My research team recently invented a way to determine the forces at work in cells and tissues from time lapse movies of their motions. When this new computational modeling technique, called video force microscopy (VFM), was used to investigate ventral furrow formation in Drosophila (fruit fly) embryos, it made it possible to map the forces acting in individual cells and to track how these forces change with time. This new knowledge explained why some embryos develop normally while others acquire birth defects. Discovery Grant funding is needed so that my team can address mathematical and mechanical issues that limit the reliability and general applicability of this promising technique. For example, if cells in mono-layer sheets are driven simultaneously by contractions along their edges and top surfaces, our current VFM algorithms can have difficulty distinguishing the contributions of each. We want to resolve these issues and use VFM to study wound healing and other important cell and tissue movements. We hope that VFM will become a standard tool for the study of cell and tissue mechanics, and we hope that it will lead to improved strategies for prevention of birth defects and cancer metastasis and give rise to new approaches in tissue engineering.