Note: This is a virtual presentation. Here is the link for where the presentation will be taking place.
Title: Stochastic Models of Chemotaxing Signaling Processes
Abstract: Stochasticity is ubiquitous in all processes. Its contribution in shaping the output response is not only restricted to systems involving entities with low copy numbers. Intrinsic fluctuations can also affect systems in which the interacting species are present in abundance. Chemotaxis, the migration of cells towards chemical cues, is one such example. Chemotaxis is a fundamental process that is behind a wide range of biological events, ranging from the innate immune response of organisms to cancer metastasis. In this dissertation, we study the role that stochastic fluctuations play in the regulatory mechanism that regulates chemotaxis in the social amoeba Dictyostelium discoideum. It has been argued theoretically and shown experimentally that stochastically driven threshold crossings of an underlying excitable system, lead to the protrusions that enable amoeboid cells to move. To date, however, there has been no good computational model that accurately accounts for the effects of noise, as most models merely inject noise extraneously to deterministic models leading to stochastic differential equations. In contrast, in this study, we employ an entirely different paradigm to account for the noise effects, based on the reaction-diffusion master equation. Using a modular approach and a three-dimensional description of the cell model with specific subdomains attributed to the cell membrane and cortex, we develop a detailed model of the receptor-mediated regulation of the signal transduction excitable network (STEN), which has been shown to drive actin dynamics. Using this model, we recreate the patterns of wave propagation seen in both front- and back-side markers that are seen experimentally. Moreover, we recreate various perturbations. Our model provides further support for the biased excitable network hypothesis that posits that directed motion occurs from a spatially biased regulation of the threshold for activation of an excitable network.
Here we also consider another aspect of the chemotactic response. While front- and back-markers redistribute in response to chemoattractant gradients, over time, this spatial heterogeneity becomes established and can exist even when the external chemoattractant gradient is removed. We refer to this persistent segregation of the cell into back and front regions as polarity. In this dissertation, we study various methods by which polarity can be established. For example, we consider the role of vesicular trafficking as a means of bringing back-markers from the front to the rear of the cell. Then, we study how BAR-domain proteins that are sensitive to membrane curvature, can amplify small shape heterogeneities leading to cell polarization. Finally, we develop computational models that describe a novel framework by which polarity can be established and perturbed through the alteration of the charge distribution on the inner leaf of the cell membrane.