Cells interact with each other and their environment through myriad membrane associated receptors and signaling molecules. In addition to individual receptor-ligand binding, spatial rearrangement of receptors into complex patterns (synapses) is rapidly emerging as a broadly significant aspect of cell recognition. Two prominent examples, which will be the foci of this investigation, are the T-cell and NK-cell immunological synapses. The PI's are mounting a quantitative investigation of the physical characteristics and principles governing the reorganization events that lead to synapse formation. They have developed a theoretical model, which compares well with experimental observations, and suggests that the essential features of immunological synapse formation are the result of spontaneous self-organization processes. Here, they propose to test and develop this hypothesis. A three-pronged investigative platform, that combines sophisticated theoretical calculations and computer simulations with novel membrane experiments in reconstituted lipid membranes and living cells, has been formulated to meet the specific aims.
In aim 1, they develop sophisticated theoretical and computational tools, and use these methods and experiments to understand the differential morphology of T cell and NK cell synapses.
In aim 2, they perform a stability analysis of their model and this, in conjunction with experiments, will allow them to study how key cell surface parameters regulate synapse formation.
In aim 3, they determine the effects of regulatory factors within the cell on synapse formation.
In aim 4, will use a genetic algorithm to explore other synaptic patterns and will perform experiments to determine if such patterns can be observed based on the current vocabulary of known molecular interactions and cell types, or based on synthetic interactions. These studies will provide a deep and quantitative understanding of synaptic pattern formation in the immune system and may lead to novel biomimetic and therapeutic approaches.
