Integration of topographical, mechanical and biochemical signals in cell motility

在这个提议中，pi将研究高运动细胞，如模式生物盘状盘基骨柱如何决定其向前运动的方向。pi将考虑到周围环境的所有信息来研究这个问题，并将整合不同类型的信号——表面地形、周围环境施加的机械力以及生化信号。pi将集中研究地形，机械和生化信号一起在同一个细胞。他们的目标是开发定量实验，以便与简单、易于处理的模型进行比较，以研究细胞的机械和生化途径之间的耦合。他们将使用全息激光镊子握住的功能化珠子，对生化和机械途径施加小的局部扰动，并测量细胞的假定上游和下游响应。此外，他们将制造受控地形的表面，以产生大规模的扰动。测量的细胞反应将与暴露于类似扰动的关键信号分子的基于反应扩散的模型系统的模拟进行比较。这种摄动分析对信号通路的结构很敏感，并将允许验证耦合的地形，机械和生化途径。这项工作将培养定量科学家从事物理学和生物学交叉领域的工作。作为该项目的一部分，pi将开发有关细胞运动的示范材料。这些演示将用于本科课程、大学开放日和公开讲座。本科生将参与拟议的研究。这些私立大学将通过指导当地高中生、参观实验室以及由数学和物理科学学院支持的项目，积极招募和帮助保留代表性不足的少数族裔。对机械和生化信号整合的理解将有助于设计更好的药物和新方法来控制细胞分化、组织形成、器官发育或生化和机械信号紧密耦合的其他过程。

In this proposal the PIs will investigate how highly motile cells such as the model organism Dictyostelium discoideum determine its forward direction of motion. The PIs will investigate this question taking into account all information about their surrounding and will integrate signals of different type - surface topography, mechanical force exerted by their surrounding as well as biochemical signals. The PIs will focus on the study of topography, mechanical and biochemical signals together in the same cell. Their goal is to develop quantitative experiments amenable to comparison to simple, tractable models for the coupling between the mechanical and biochemical pathways of the cell. They will apply small local perturbations to both biochemical and mechanical pathways using functionalized beads held by holographic laser tweezers, and measure both putative upstream and downstream responses of the cell. In addition, they will fabricate surfaces of controlled topography to generate large scale perturbations. The measured cell response will be compared with simulations of reaction diffusion based model systems of the key signaling molecules exposed to similar perturbations. Such perturbation analysis is sensitive to the structure of the signaling pathways, and will allow the validation of the coupled topographical, mechanical and biochemical pathways. This work will train quantitative scientists for interdisciplinary work at the interface of physics and biology. As part of this project the PIs will develop demonstration materials on cell motility. These demos will be used in undergraduate courses, university open houses, and public lectures. Undergraduate students will be involved in the proposed research. The PIs will actively recruit and aid in retention of underrepresented minorities through mentoring of local high school students, lab tours, and programs supported by the College of Math and Physical Sciences. The understanding of the integration of the mechanical and biochemical signals will help in designing better drugs and new approaches to control cell differentiation, tissue formation, organ development, or other processes where biochemical and mechanical signals are tightly coupled.