CAREER: Mechanobiology of Septins in the Cytoskeleton

了解细胞如何操纵自身材料特性的机制将为治疗疾病和开发新的工程材料提供新的方法。构成生物体的细胞和组织就像任何其他物质一样具有物质特性。当受到机械力，如拉或推时，它们会拉伸并改变形状。它们甚至可以自己产生这些力。细胞的物质特性是由细胞骨架（一组丝状蛋白质）控制的。这种纤维网络决定了细胞的形状，就像骨骼决定了人的形状一样。然而，在细胞中，这个网络是动态的和自适应的，它自我重组以帮助细胞执行各种功能或抵抗外部机械应力。因此，细胞骨架代表了一种不服从传统工程材料模型的新型材料。它可以在空间和时间上调节其物质特性。该学院早期职业发展计划（Career）项目将确定细胞如何能够在空间和时间上调节其材料特性，并发掘可用于开发新工程材料和了解某些疾病如何影响细胞行为的新设计原则。在物理学、生物学和工程学之间，这项多学科的工作将为广泛领域的研究提供信息。最重要的是，它将为各种各样的学生和年轻研究人员创造机会，发展创新的技能和观点，特别是学习跨学科交流新颖的方法和思想。细胞骨架是一个模型系统，用于发展对非平衡力学和网络动力学的见解，并且已知既产生又响应机械信号。尽管事实上主要的分子生化相互作用已经很详细，但我们仍然缺乏对宏观尺度行为如何从许多分子相互作用的集合中产生的理解。septin是研究最少的组成细胞骨架的细丝。它们与肌动蛋白和质膜结合，并被证明特异地定位于肌动蛋白曲率和机械应力区域。该研究项目将测试septin通过改变局部结构来帮助调节细胞骨架的材料特性的假设。这项工作将测量活细胞和纯化蛋白网络中septin-actin网络的材料特性，并测试这些网络对机械扰动的响应，如控制细胞形状的微图案，牵引力显微镜和光遗传学诱导局部收缩。除了潜在地揭示调节细胞形状的新机制外，这项工作还将深入了解网络中的分子相互作用如何整合到宏观行为中。该奖项反映了美国国家科学基金会的法定使命，并通过使用基金会的知识价值和更广泛的影响审查标准进行评估，被认为值得支持。

Understanding the mechanisms of how cells manipulate their own material properties will provide new ways to treat disease and a way to develop new engineering materials. The cells and tissues that make up living organisms have material properties just like any other substance. When exposed to mechanical forces, such as pulling or pushing, they stretch and change shape. They can even generate these forces themselves. The material properties of cells are controlled by the cytoskeleton, a collection of filamentous proteins. This network of filaments gives cells their shape, much like the skeleton defines the human shape. In cells, however, this network is dynamic and adaptive, reorganizing itself to help cells perform various functions or to resist outside mechanical stresses. The cytoskeleton thus represents a new class of material that doesn't obey the traditional models of engineering materials. It can modulate its material properties in both space and time. This Faculty Early Career Development Program (CAREER) project will determine how the cell is able to spatially and temporally regulate its material properties and unearth novel design principles that can be used to develop new engineering materials and to understand how some diseases affect cell behavior. Sitting at the interface between physics, biology, and engineering, this multi-disciplinary work will inform research across a broad spectrum of fields. Most importantly, it will create opportunities for a diverse set of students and young researchers to develop innovative skills and perspectives, in particular learning to communicate novel methods and ideas across disciplines. The cytoskeleton is a model system for developing insights into non-equilibrium mechanics and network dynamics, and is known to both generate and respond to mechanical signals. Despite the fact that the principal molecular biochemical interactions have been well detailed, we still lack an understanding of how macroscopic scale behaviors emerge from the collection of many molecular interactions. Septins are the least studied filaments that make up the cytoskeleton. They bind to both actin and the plasma membrane, and have been shown to localize specifically to regions of actin curvature and mechanical stress. This research project will test the hypothesis that septins help to regulate the material properties of the cytoskeleton by altering the local architecture. This work will measure the material properties of septin-actin networks in both living cells and purified protein networks, and test the response of these networks to mechanical perturbations such as micropatterning to control cell shape, traction force microscopy, and optogenetics to induce local contractions. In addition to potentially uncovering novel mechanisms to regulate cell shape, this work will also generate insight into how molecular interactions in a network are integrated into macroscopic behaviors.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.