Modeling Biophysical Mechanisms underlying Cellular Homeostasis

............................................................................................................................... v List of papers ........................................................................................................................ ix Summary of papers and author contribution ......................................................................... x Introduction and Background ................................................................................................ 1 1. Biological physics and cellular biophysics ....................................................................................... 1 2. Modeling ......................................................................................................................................... 1 Classical modeling ........................................................................................................................... 2 Non-classical modeling but very classical scientific strategy .......................................................... 2 3. Cellular homeostasis ....................................................................................................................... 3 Cell membrane, volume and electrical potential ............................................................................ 3 Perturbation in the extracellular space .......................................................................................... 4 Biophysical homeostasis ................................................................................................................. 4 4. Morphology of cells and geometrical modeling ............................................................................. 4 5. Diffusion .......................................................................................................................................... 5 Diffusion Limited Space (DLS) ......................................................................................................... 5 6. Transport proteins .......................................................................................................................... 6 Water channels ............................................................................................................................... 6 K channels ...................................................................................................................................... 8 Cl channels ..................................................................................................................................... 8 7. Kidney principal cells and DLS ......................................................................................................... 9 K excretion and K recycling ........................................................................................................... 9 8. Astrocytes and DLS .......................................................................................................................... 9 K spatial buffering and K siphoning ............................................................................................ 10 Aquaporins and Kir channels in astrocyte membranes ................................................................ 10 Cortical spreading depression (CSD) ............................................................................................. 11 Importance of diffusion in the extracellular space ....................................................................... 11 9. Mesoporous silica particles and DLS ............................................................................................. 11 Methods and Results ........................................................................................................... 13 1. The Main Toolbox ......................................................................................................................... 13 I) Transport mechanisms .............................................................................................................. 14 II) Confocal microscopy ................................................................................................................. 16 Modeling biophysical mechanisms underlying cellular homeostasis viii III) Fluorescence intensity and molecular release ........................................................................ 17 IV) Virtual cell modeling software ................................................................................................. 19 2. Methods and results of different papers ...................................................................................... 19 Paper I) .......................................................................................................................................... 19 Paper II) ......................................................................................................................................... 21 Paper III) ........................................................................................................................................ 22 Paper IV) ........................................................................................................................................ 23 Paper V) ......................................................................................................................................... 25 Paper VI) ........................................................................................................................................ 27 3. A key result.................................................................................................................................... 28 Biophysical functional couplings between water and K channels in DLS .................................... 28 Discussion and Conclusion ................................................................................................... 31 From morphology to homeostasis .................................................................................................... 31 From homeostasis to morphology .................................................................................................... 32 Modeling perspectives ...................................................................................................................... 32 Example 1. DLS modeling .............................................................................................................. 33 Example 2: ECS modeling .............................................................................................................. 33 Conclusion ......................................................................................................................................... 34 Acknowledgements ............................................................................................................. 35 References .......................................................................................................................... 41 Appendix A .......................................................................................................................... 46