This effort represents a new multidisciplinary research initiative focused on the immune system, with an emphasis on quantitative, computer-based, microscopic and macroscopic modeling of immune functions, integration of these modeling efforts with data sets derived from global analyses of cell components, and the development and application of advanced imaging methods to the analysis of immune responses in vivo in models systems, and ultimately, man. The program is designed to deal with the existing lack of any large-scale effort to understand the ?engineering? of the immune system from the biochemical through the organismal levels and to generate predictive models based on such understanding.? ? The overall goal of the Program In Systems Immunology and Infectious Disease Modeling (PSIIM) will be the development of a new level of integrated understanding of how the immune system functions and how it interacts with pathogens. The primary imperative would be accumulation of the specific information necessary to devise robust quantitative, predictive models of immune behavior in various circumstances, including exposure to infectious agents, following vaccine administration, or in autoimmune diseases. A key effort will be the implementation of the type of measurement rigor needed for effective modeling at all levels of immune organization, from the biochemical to the whole animal. ? ? The second key goal will be the development and distribution of modeling / simulation software that is amenable to ready adoption by bench biomedical researchers lacking mathematical sophistication. Success in this area accompanied by broad availability of these programs will empower intramural and extramural scientists supported by more traditional RO1-type mechanisms to move into a new era of quantitative, predictive (immuno)biology without requiring either extensive re-training in mathematics or the development of often hard-to-arrange collaborations with professional mathematicians. This goal is fully congruent with the aims of the Roadmap Initiative in Biocomputing.? ? During the past year, we have refined a first generation software suite that allows detailed, spatially-resolved computer simulation of transmembrane and intracellular signaling events. This package also allows higher-order rules- based modeling on the whole cell level. The models used for the simulations are created using simple graphical interfaces, number entry, and click-and-drag methods familiar to most biologists. Complete signaling networks are automatically created by the program from binary protein interactions specified by the user. The output of the simulations is available in a variety of formats, including a browser that allows the user to follow the flux through the signaling network at any specified level of resolution. Using these new software tools, we have implemented a detailed biochemical model of Dictyostelium discoideum chemosensing and demonstrated that the simulated behavior of these amoeba as determined using the program accurately predicts in time and space the actual response of these organisms to an applied chemoattractant gradient of cAMP. Additional progress has been made in the development of new methods for ?adaptive gridding? of modeled cells, allowing much higher resolution in certain regions of the cell during simulations and in modeling the tension and shape of flexible membranes, a key development in modeling cell motility and the effects of the cytoskeleton on plasma membrane behavior.
