Physics of Centrosome Reorientation during Signaling Activation in Immune Cells

University Of Maryland, College Park, College Park MD

Investigators

Abstract

The immune system is an important defense mechanism against infections and cancer. T cells are central effectors of the adaptive immune response. They recognize molecules on the surface of cells, and initiate signaling that results in the immune response. An essential step during this process is the reorientation of the T cell microtubule-organizing center (centrosome). Proper positioning of the centrosome is required for normal signaling through the T cell receptor and the directed release of lymphokine molecules in T helper cells or cytotoxins in cytotoxic T cells. While the signaling pathways between T cell activation and centrosome positioning have been well studied, the physical mechanisms underlying asymmetric centrosome positioning are not understood. The PI will combine quantitative imaging and biophysical measurements with molecular dynamics simulations to unravel the role of cytoskeletal forces in centrosome positioning. The PI will develop a course on Biophysics of the Cell covering topics ranging from cytoskeletal forces to mechano-chemistry of signaling. Research results from the proposed projects will be used to develop a novel laboratory component. The PI and co-PI will offer a beginning undergraduate course focused on introducing students to concepts of critical thinking and research practice using hands on research experience on relevant themes such as cellular force generation. The PI and co-PI will mentor graduate and undergraduate student research and encourage minority students and high school students from the area to participate in research. The PI will organize a week-long biophysics lab demonstration as part of the Summer Girls Program in the Physics Department to encourage participation of female high school students in science. The co-PI will develop user friendly educational software modules teaching how complex cytoskeletal dynamics emerges from simple molecular interactions. These studies, using an integrated experimental and computational approach, will lead to fundamental understanding of centrosome positioning which is critical in many cellular functions in many cell types. The group will use state-of-the-art imaging techniques to quantitatively analyze the 3-dimensional shape and dynamics of microtubules. In parallel, they will develop a computational model of centrosome movement driven by MT dynamics and motor activity. Model parameters will be set by comparisons with experimental observations (Objective 1). The PI will investigate the interactions between the acto-myosin cytoskeleton and the MT-dynein systems and their respective roles in centrosome positioning. The PI will also extend the model to include both actin and microtubule cytoskeletons and associated motors, their mutual couplings and systematically model perturbations carried out in parallel experiments (Objective 2). This research will unravel novel physical principles involved in the collective dynamics of two distinct but interacting force-generating biopolymer filament systems and associated motors. The development of the mechano-chemical model will be applicable to many other phenomena in cell biology and hence a valuable contribution to the field. More broadly, this work will provide novel insights on the principles of self-organization in highly complex active matter systems. This project is being jointly supported by the Physics of Living Systems program in the Division of Physics and the Cellular Cluster in the Division of Molecular and Cellular Biosciences.