Stochastic mathematical-computational simulations to unravel mechanical relations of fluid flow and influence of actin regulators on filopodial dynamics

• Autor(a) principal: Leal, Thiago Franco
• Data de Publicação: 2020
• Tipo de documento: Tese
• Idioma: eng
• Título da fonte: Biblioteca Digital de Teses e Dissertações da UERJ
• Texto Completo: http://www.bdtd.uerj.br/handle/1/17798
• topic: Mechanical engineering; Transport theory; Stochastic process; Actin; Engenharia mecânica; Teoria do transporte; Processo estocástico; Actina; ENGENHARIAS::ENGENHARIA MECANICA::FENOMENOS DE TRANSPORTE

Actin is the most abundant protein in eukaryotic cells which forms filamentous polymers (F-actin) that get arrange into networks providing the skeleton of cells and play vital roles in many cellular functions. For example, prominent parallel bundles of F-actin mediate the formation and dynamics of filopodia, which are long, finger-like membrane protrusions of cells or growing nerve cells. Filopodia have important functions in cell migration and communication relevant for neural development, aging, degeneration, and regeneration. In filopodia, F-actin undergoes constant "treadmilling", i.e. backflow of the entire F-actin bundle driven by their polymerization at the distal tip of filopodia and their concomitant disassembly at the base of filopodia. An amount of actin-regulating proteins is known to mediate and regulate these processes. In addition, large amounts of monomeric G-actins are required as building blocks at the very tip of filopodia and need to travel through the entire length of the confined, narrow lumen of filopodia. To understand the mechanic basis of actin treadmilling in filopodia, this work presents an alternative stochastic model formulation to simulate molecule displacement. Unlike previous attempts, it considers not only diffusion as the essential transport mode, but adds cytoplasmic flow towards the tip (occurring to replace volume taken out by the back-flowing actin filaments), but also the specific properties and affinities of actin regulators, in particular, profilin and Ena/VASP. Integrated implementation of these physical and biochemical parameters into one computational model was possible by using particle-centered simulations, an approach that seems to be unprecedented in biological modeling. When applying this particle-centered model, filopodia grow up to about 40 µm in length, sub-filopodial flow dynamics can be deduced, and it allows to test how the different parameters contribute to filopodial dynamics. Also, it has the capacity to be refined by gradually adding more or improved parameters obtained from biological or physical studies, thus serving as an iterative medium of prediction and validation. The particle-centered model developed here clearly demonstrates the potential of this strategy for the wider application to biological problems.