Adaption of mechano-chemical self-organization at cellular membranes to extracellular stressors

质膜受到长度和幅度变化的连续变形。响应于这种瞬时膜变形，曲率敏感分子被动态地募集到这些位点。 与这个提议相关的是，这些蛋白质中的一些能够局部改变肌动蛋白聚合速率，从而改变施加到膜上的力。这反过来又创造了受体独立的反馈回路。 在最近的工作中，我们鉴定了这样一种曲率依赖性模块，其介导粘附单细胞中的探索性搜索模式（Begemann et al.，Nature Physics）。 我们发现，这种自组织模块依赖于曲率敏感信号分子在前缘（LE）处变形膜的动态招募，改变了包括免疫细胞在内的各种单细胞模型系统中的运动模式。 然而，外部应激源对信号处理的影响，以及因此对通过该模块的搜索模式的影响，仍然难以捉摸。 在这个项目中，我们的目标是研究这些输入如何影响信号和细胞运动。 具体来说，我们将回答（i）温度如何改变曲率依赖的细胞运动模式，以及（ii）基底刚度如何影响曲率依赖的细胞运动模式。为了解决这些问题，我们将利用我们在实验室开发的最先进的细胞，生物物理和计算工具。 总的来说，这些研究将使我们能够获得新的见解的基本问题，自组织信号系统如何适应不同的外部条件下的运动模式的信号。

The plasma membrane is subject to continuous deformations that vary in length and amplitude. In response to such transient membrane deformations, curvature-sensitive molecules are dynamically recruited to these sites. Relevant for this proposal, some of these proteins are capable to locally change actin polymerization rates, and in consequence the force exerted to the membrane. This, in turn, creates receptor-independent feedback loops. In recent work, we identified such a curvature-dependent module that mediates exploratory search pattern in adherent single cells (Begemann et al., Nature Physics). We showed that this self-organizing module, which relies on dynamic recruitment of curvature-sensitive signaling molecules to deforming membranes at the leading edge (LE), alters motion pattern in a variety of single-cell model systems including immune cells. However, the consequences of external stressors on signal processing, and hence on search pattern via this module, have remained elusive. In this project, we aim to investigate how such inputs affect signaling and cell motion. Specifically, we will answer (i) how temperature alters curvature-dependent cellular motion pattern, and (ii) how substrate stiffness affects curvature-dependent cellular motion pattern. To address these questions, we will take advantage of state-of-the-art cellular, biophysical and computational tools that we developed in the lab. Collectively, these studies will allow us to gain novel insights into the fundamental question how a self-organizing signaling system adapts signaling for motion pattern under varying external conditions.