The response of cells to their environment is driven by a variety of proteins and messenger molecules. In eukaryotes, their distribution and location in the cell is regulated by the vesicular transport system. The transport of aquaporin 2 between membrane and storage region is a crucial part of the water reabsorption in renal principal cells, and its malfunction can lead to Diabetes insipidus. To understand the regulation of this system, I aggregated pathways and mechanisms from literature and derived models in a hypothesis-driven approach. Furthermore, I combined the models to a single multi-scale model to gain insight into key regulatory mechanisms of aquaporin 2 recycling. To achieve this, I developed a computational framework for the modeling and simulation of cellular signaling systems. The framework integrates reaction and difusion of biochemical entities on a microscopic scale with mobile vesicles, membranes, and compartments on a cellular level. The simulation uses an adaptive step-width approach that e ciently regulates the agent-based simulation of macroscopic components with the numerical integration of mass action kinetics and grid-based nite diference methods. A reaction network generation algorithm was designed, that, in combination with a highly-modular modeling approach, allows for fast model prototyping. The analysis of the aquaporin 2 model system rationalizes that the compartmentalization of cAMP in renal principal cells is a result of the protein kinase A signalosome and can only occur if speci c cellular components are observed in conjunction. Endocytotic and exocytotic processes are inherently connected and can be regulated by the same protein kinase A signal.:Abstract
1. Introduction
1.1. Eukaryotic Signaling
1.2. Modeling and Simulation of Cellular Processes
1.3. Aquaporin 2 recycling
1.4. Motivation and Aims
1.5. Outline
I. Background
2. Modeling and Simulation of Complex Signaling Pathways
2.1. Multi-scale Modeling
2.1.1. Approaches to Multi-scale Modeling
2.1.2. Reduction of Computational Complexity
2.2. Models of Chemical Reaction Networks
2.2.1. Reactions and Reaction Rates
2.2.2. Numerical Solutions
2.2.3. Reaction Network Generation
2.3. Models of Intracellular Transport
2.3.1. Undirected Transport
2.3.2. Directed Transport
3. Aquaporin 2 Recycling in Renal Principal Cells
3.1. The Physiology of Water Homeostasis
3.2. Molecular Mechanisms of the Vasopressin Response
3.2.1. The Vasopressin Receptor
3.2.2. cAMP Regulation of Protein Kinase A
3.2.3. Endo- and Exocytosis
3.3. Models of Water Transport in Renal Principal Cells
II. Results & Discussion
4. Multi-scale Simulation of Cellular Signaling Pathways
4.1. Scale Separation and Bridging
4.2. Micro-scale Simulation Approach
4.2.1. Difusion and Discretization of the Simulation Space
4.2.2. Reaction Kinetics
4.3. Rule-based Reaction Network Generation
4.3.1. Definition of the Data Model
4.3.2. Design of Rule Based Reactions
4.3.3. Automated Generation of Reaction Networks
4.4. Macro-scale Simulation Approach
4.4.1. Agent-based Simulation of Discrete Entities
4.4.2. Modules for Displacement-based Behavior
4.5. Modularization and Error Estimation
4.5.1. Determination of the Numerical Error
4.5.2. Modularization of Concentration-based Events
4.5.3. Determination of the Displacement-based Error
5. Aquaporin 2 Recycling Model and Simulation
5.1. Model of Allosteric PKA Phosphorylation
5.1.1. Model Design
5.1.2. Simulation Results and Discussion
5.1.3. Conclusions
5.2. cAMP Compartmentalization in the Vesicle Storage Region
5.2.1. Model Design
5.2.2. Simulation Results and Discussion
5.2.3. Conclusions
5.3. Clathrin-mediated Endocytosis
5.3.1. Model Design
5.3.2. Simulation Results and Discussion
5.3.3. Conclusions
5.4. Intracellular Transport and Recycling
5.4.1. Model Design
5.4.2. Simulation Results and Discussion
6. Conclusion
6.1. Modeling and simulation approach
6.2. Insights into the AQP2 recycling model
III. Appendix
A. Code Availability
B. Module Overview
Bibliography
| Identifer | oai:union.ndltd.org:DRESDEN/oai:qucosa:de:qucosa:82767 |
| Date | 22 December 2022 |
| Creators | Leberecht, Christoph |
| Contributors | Schroeder, Michael, Labudde, Dirk, Technische Universität Dresden, Hochschule Mittweida |
| Source Sets | Hochschulschriftenserver (HSSS) der SLUB Dresden |
| Language | English |
| Detected Language | English |
| Type | info:eu-repo/semantics/publishedVersion, doc-type:doctoralThesis, info:eu-repo/semantics/doctoralThesis, doc-type:Text |
| Rights | info:eu-repo/semantics/openAccess |
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