CAREER: Mechanobiology of Septins in the Cytoskeleton

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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.