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Innovative Tools for Three Dimensional Traction Force Microscopy of Single Cells

单细胞三维牵引力显微镜的创新工具

基本信息

批准号：
9465846
负责人：
Ottmar Klaas
金额：
$ 14.94万
依托单位：
SIMMETRIX, INC.
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-21 至 2019-03-20
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9465846
关键词：
Accounting Algorithms Alpha Cell Atherosclerosis Atomic Force Microscopy Behavior Benchmarking Biochemical Biological Biology Biomechanics Breast Cancer Cell Cell Shape Cell physiology Cells Chronic Code Communities Computer Systems Computer software Computer-Aided Design Custom Data Set Development Dimensions Disease Progression Elements Embryonic Development Event Extracellular Matrix Fibroblasts Gel Generations Heterogeneity Human Individual Lead Link Malignant Neoplasms Measurable Measures Mechanics Methods Microspheres Modeling Pathway interactions Performance Physics Physiological Play Population Process Property Research Resolution Role Signal Transduction Software Design Spatial Distribution Specific qualifier value Techniques Tissues Traction Variant biological systems cancer cell cell motility cell type computer program design improved innovation insight novel novel therapeutic intervention optical imaging response software development stem cell differentiation tool

项目摘要

Project Summary Tractions exerted by individual cells on their surroundings play a critical role in mechanical events in biology such as tissue contraction, folding, cell shape changes, or cell movements, and in many basic cellular functions such as biochemical signaling, proliferation, and differentiation. These processes are in turn implicated in the progression of diseases like cancer, atherosclerosis, and other chronic fibrotic conditions. Recently, this remarkable link has been utilized to develop exciting new therapeutic interventions that rely on disrupting mechano-signaling machinery within the cell, and the pathways that lead to the remodeling of the extra-cellular matrix (ECM). Techniques that can precisely quantify the spatial variation and heterogeneity of cellular traction within and between cells have found important applications in understanding and controlling these processes. Of these, three-dimensional traction force microscopy (3D TFM) has emerged as a particularly valuable tool since it is applied to cells embedded in a three-dimensional ECM, the natural state for most cells. Current 3D TFM approaches are challenged by the critical steps of using optical images to generate a 3D geometrical model of the matrix surrounding the cell, and inferring cellular tractions from displacement estimates of micro-beads embedded in the matrix. Approximations incurred in these steps lead to significant errors in computed tractions that in turn lead to erroneous biological conclusions. Thus there is critical need to develop more accurate and high resolution 3D TFM techniques. The long-term objective of the proposed research is to improve and automate the 3D TFM process so that it can be effectively used to answer mechanobiological questions and design new therapeutic interventions. This will be accomplished by (a) applying advanced segmentation and mesh generation techniques to optical images to generate 3D geometric models and finite element meshes of the matrix surrounding a cell, and (b) by developing and implementing new algorithms to determine the spatial distribution of cellular tractions from measured micro-beads displacements, while accounting the nonlinear elastic response of the matrix. These developments will be validated through benchmark studies, and their utility will be demonstrated by quantifying the traction exerted by cancer cells embedded in a synthetic extracellular matrix.

项目摘要在生物学中，单个细胞对周围环境施加的牵引力在机械事件中起着关键作用例如组织收缩、折叠、细胞形状改变或细胞运动，并且在许多基本细胞中，生物化学信号传导、增殖和分化等功能。这些过程反过来与癌症、动脉粥样硬化和其他慢性纤维化病症等疾病的进展有关。最近，这种显著的联系已被用于开发令人兴奋的新的治疗干预措施，扰乱细胞内的机械信号机制以及导致细胞重塑的途径细胞外基质（ECM）。技术，可以精确地量化空间变化和异质性的细胞牵引内，在理解和控制这些过程中发现了重要的应用。其中，三维牵引力显微镜（3D TFM）已经成为一种特别有价值的工具，因为它应用于嵌入三维ECM中的细胞，这是大多数细胞的自然状态。当前3D TFM 这些方法受到使用光学图像来生成三维几何模型的关键步骤的挑战。细胞周围的基质，并从微珠的位移估计推断细胞牵引力嵌入在矩阵中。在这些步骤中产生的近似导致计算牵引力的显著误差从而导致错误的生物学结论。因此，迫切需要开发更准确和高分辨率三维TFM技术。拟议研究的长期目标是改进和自动化3D TFM过程，可以有效地用于回答机械生物学问题和设计新的治疗干预措施。这将通过（a）将先进的分割和网格生成技术应用于光学图像，以生成围绕细胞的基质的3D几何模型和有限元网格，以及（B）通过开发和实施新的算法来确定细胞牵引力的空间分布，测量微珠位移，同时考虑基体的非线性弹性响应。这些开发将通过基准研究进行验证，其效用将通过量化嵌入合成细胞外基质的癌细胞所施加的牵引力。