PROPOSAL NO.: CTS-0625599 PRINCIPAL INVESTIGATOR: K. SARKAR INSTITUTION: U OF DELAWARE
Simulation of Leukocyte Adhesion Cascade: Effects of Cell Deformation and Hydrodynamic Interactions between Cells
The migration of leukocytes (white blood cell) from post capillary blood stream to the site of infection is the key step in human body's inflammation responses. The migration process involves a sequence of leukocyte-blood-vessel interactions called the leukocyte adhesion cascade (LAC). Each step in the cascade (leukocyte margination, rolling, firm adhesion and final transmigration) involves not only the chemical and signaling events at the molecular level, but also the fluid and interface motion, shape evolution and cell-cell interactions. The goal of this grant is to develop a comprehensive computational model and to simulate the leukocyte adhesion cascade. The focus is on a systematic investigation of the hydrodynamic effects of cell deformation and cell-cell interactions in the rolling process and development of a model of the transmigration step of the cascade when the leukocyte squeezes out of the endothelial cell junctions. Current models are mostly focused on the physical chemistry of local molecular adhesion, neglecting the cell deformation and hydrodynamics. The flow and deformation of blood cells are important aspects regulating the adhesion cascade. Among the specific objectives is to develop a comprehensive 3D model for viscoelastic cells with membrane and molecular bindings, including the surface and bulk rheology of cells, and transmigration of leukocyte through cell junctions and molecular bindings. This computational platform will develop critical understanding of the recruitment and subsequent emigration of leukocytes into inflamed tissue, which occurs virtually in every organ. It will help develop improved methodologies for diagnosis and treatment of immunodeficiency and inflammation related diseases, including atherosclerosis and rheumatoid arthritis. Under this grant ME undergraduate and graduate students will be trained in the non-traditional cross-disciplinary interface of biology and mechanics. The PI has established a link with a collaborator in Morgan State University (an HBCU) to identify talented undergraduate research internships and to groom them for graduate study at the University of Delaware.
