Cells interact and respond to their surroundings, and the adhesion - or contact force - between cells and their surroundings is an important feature of this interaction. This adhesion is the result of surface receptors on the cells called integrins. In tissues and organs, cellular adhesion plays a role in normal and abnormal physiology. As a result, cell adhesion is likely to play a role in disease processes such as cancer, infection, inflammation, and blood clotting. If cell adhesion can be understood, and subsequently controlled, it may lead to new insights into biotechnology or treatment strategies. While previous research has focused on a single bond, or connection, between a cell and its surrounding, it is known that it is actually a cluster of these bonds that governs cellular adhesion. This project seeks to develop a fundamental understanding of how the size and shape of clusters of bonds affect the strength and behavior of the adhesion. A combination of experiments, using a novel approach called DNA origami, and computational modeling will be used to address these fundamental questions. In addition, the project seeks to expand interest in STEM and an understanding of how engineers can support their communities through a series of K12 outreach activities as well as by integrating the research focus and outreach activities into undergraduate engineering coursework.
This project will use the bond between platelet glycoprotein Ib (GPIb) and the blood protein von Willebrand Factor (VWF), both of which are involved in blood clotting, as a model system to study the behavior of clusters of catch bonds. It is hypothesized that the strength of the bonds between GPIb and a specific region of VWF will vary significantly based on the size and geometry of the clusters, which allows a single molecular bond to perform a range of functions based on these variations. DNA origami, which can control the attachment of molecules in specific quantities and locations, will be used to experimentally investigate this hypothesis. This novel method will be combined with measurements of adhesion force using atomic force microscopy and the development of computer simulations. Three aims have been established: 1) to determine whether clusters of molecular bonds have catch, slip, or ideal behavior; 2) to determine how clusters of these bonds contribute to shear-enhanced rolling adhesion in VWF; and 3) to determine how clusters of these bonds contribute to stable platelet adhesion. Thus, the integrated modeling and experimental approach will provide key insights into both fundamental cellular adhesion biomechanics along with these processes in a specific physiological process, blood clotting.
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.
