Funding entity Ministerio de Ciencia e Innovación (MCIN), Agencia Estatal de Investigación (AEI), 10.13039/501100011033
Participated by University of Leeds, Universidade de Vigo, Universidade de Lisboa
The immune response involves multiple stages operating at different spatial and temporal scales. In recent years there has been increasing recognition of the role of physical processes in the effectiveness of the response, starting with the region of physical contact between cells (the so-called immunological synapse). In general, it is not possible to speak of the immune response at a scale but an interaction between scales. On the other hand, although the exact molecular structure of the T cell receptor was discovered in August 2019, this knowledge does not fully determine the immune response as it is a dynamic process out of equilibrium, which requires the use of the traditional tools of statistical physics.
The central objective of the project is to quantify through modeling, simulation, and data analysis the role of the biophysical aspects of the immune response operating at different scales, always focusing on the explanation of experimental data, discrimination between alternative theories and the generation of new hypotheses. To achieve this objective, a study is proposed separating these scales and choosing the methodology that best adapts to their characteristics (large/small concentrations, fluctuations, spatial properties versus well-mixed, etc...) and the available experimental data.
At the molecular level, we will model the cooperation of T-cell receptors (TCR) to determine the dominant mechanism in the amplification of sensitivity by TCR nanoclusters. Combining stochastic models, image analysis and Bayesian inference, we will quantify the dynamics and function of these nanoclusters. This approach will extend to cytokine-activated competition processes.
At the cellular level, we propose the quantitative study of cell deformation at the synapse. In the first phase, we will use an experimental model of a collaborating group (hydrothermal carbon) to validate simulation models based on finite elements and generate effective models of this deformation. In the second phase, we will model the cell membrane using the phase-field method. Finally, we will extend classical models of statistical physics (Smoluchowski model) to study the intracellular dynamics of organelles in viral infections.
At the population level, we will introduce compartmental models that allow us to contrast hypotheses on the maturation dynamics of T lymphocytes in the thymus, with special emphasis on symmetry/asymmetry in the selection of double negative cells, and we will use the models to extract the most parsimonious mechanism from the analysis of experimental data. Following the compartmental models, we will study the role of latency in the severity of HIV infection. The model will be contrasted with experimental data where the role of drugs reversing latency will be analyzed. At all levels, exhaustive use of statistical inference methods will be made, for which the transversal problem of the models' identifiability and new measures of sensitivity and synergy of the models' parameters will be analyzed.
The research team is multidisciplinary (Physics, Mathematics, and Mechanical engineering) and will have a work team made up of biologists, mathematicians and physicists and experimental collaborators who will provide us with empirical data to validate the models.
Grant PID2019-106339GB-I00 funded by MCIN/AEI/10.13039/501100011033/
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IMMUNEPHYS
