With NIGMS P20 support, the New Mexico Center for the Spatiotemporal Modeling of Cell Signaling (Spatiotemporal Modeling Center, STMC) has set in motion an interdisciplinary, inter-institutional program whose principal goals are: 1), to determine how the spatial proximity, dynamics, interactions and biochemical modifications of membrane receptors and signaling proteins together determine the outcome of complex, interacting cell signaling networks;2) to equip a new generation of interdisciplinary researchers for successful research careers focused on quantitative, systems level analyses of complex biomedical processes;3) to establish an effective and sustainable infrastructure to nurture and sustain systems biology research and training as a long-term area of scientific emphasis in New Mexico;and 4), to lead the advancement of women and minorities within the new discipline of systems biology. This application proposes the STMC for recognition as the first P50 National Center for Systems Biology in the Southwestern USA. The anchoring biology will remain focused on signaling through the high affinity IgE receptor (FceRI), a key player in allergies and asthma, and on the modulation of FceRI signaling by positive crosstalk with the bacteria-sensing formyl peptide receptor (FPR) and negative crosstalk with the IgG receptor, Fc?RIIB. The robust and tractable RBL-2H3 rat basophilic leukemia cell will remain the main tool for systematic quantitative measurements. The experimental team will quantify the distributions, mobility, interactions and phosphorylation/dephosphorylation of receptors and signaling proteins and lipids that occur during signaling. Membrane-proximal events will be linked in time and space to Ca2+ mobilization and to Ca2+-dependent secretion. The computational teams will develop predictive models of signal initiation at the membrane and of IP3-mediated Ca2+ mobilization leading to secretion.
In Aim 1, sophisticated rules-based modeling approaches will be applied to develop mechanistic kinetic models of early signaling events triggered by the three receptors.
In Aim 2, an agent-based 3D simulator will be used to evaluate spatial aspects of receptor signaling, including clustering, diffusion and other dynamic membrane-proximal processes.
Aim 3 will use a new stochastic spatial model, to address the impact of cellular geometry on calcium regulation, with an emphasis on coupling of ER sensors (STIMs) and store-operated channels (Orai family members) within plasma membrane-ER contact sites to support capacitative entry. Systematic dose-response studies and pharmacological and genetic manipulations will test model predictions and validate new targets for clinically-useful interventions. Access to primary human blood basophils will enable direct clinical translation. The STMC research teams have long track records of measuring and modeling FceRI signaling, crosstalk and outcomes. They also have track records of continuous innovations in technology, a tradition extended here through developments in super-resolution fluorescence microscopy, in the creation of novel fluorescent single chain Abs (scFvs) and in the engineering of microfluidic platforms for cell activation and analysis. The Center's plans for Administration, Development and Training will maximize the ability of center members to conduct innovative science and will bring new members, collaborators and minority students to the Center. Data and models will be disseminated broadly through web-based tools, an active visitor and seminar program and an annual high profile conference. The Center will strongly support translation of new technical and computational tools to other signaling systems linked to human disease, especially other immune diseases and cancer.
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