Decoding Volume Regulation Across Timescales with Ultrafast imaging and Mechanistic Modelling

Cell volume is fundamental to biological organisation, controlling molecular concentration, intracellular transport, membrane tension and cytoplasmic mechanics. Cell volume emerges from coupled osmotic and hydrostatic pressures, water movement across the membrane, intracellular poroelasticity and active ion regulation operating from milliseconds to minutes. These overlapping processes are difficult to distinguish using conventional imaging.

This interdisciplinary PhD will combine ultrafast quantitative phase imaging, microfluidic pressure control and mechanistic modelling to identify the physical parameters that govern cell-volume regulation. The project builds directly on our previous BBSRC Transformative Research Technologies award, which developed advanced QPI and open tools for mechanobiology. Operating above 300 frames per second, our label-free platform can measure the earliest volume responses before slower active regulation dominates.

The student will apply precisely controlled osmotic and hydrostatic pressure stimuli, including steps, pulses, ramps and oscillations, to living cells. These perturbations will provide a form of “pressure–volume spectroscopy”, enabling the candidate to quantify the dynamics of cellular water transport: how rapidly water crosses the plasma membrane, redistributes within the cytoplasm, and is subsequently regulated by membrane channels and pumps.

The transformative approach developed during the PhD will enable us for the first time to reveal how cells sense and respond to dynamic changes in their physical environment. A mechanistic model will couple osmotic and hydrostatic pressure, transmembrane water flux, cytoplasmic poroelasticity, membrane–cortex mechanics and active volume recovery. The model will be fitted to individual-cell trajectories to estimate parameters such as hydraulic permeability, poroelastic relaxation and regulatory transport strength. Its ability to predict responses to previously unseen pressure waveforms will provide a stringent test of the proposed mechanisms.

Experiments will compare isogenic wild-type, YAP knockout, TAZ knockout and YAP/TAZ double-knockout HEK293 cells alongside fibroblasts and adipocytes. YAP and TAZ regulate cell size and cytoplasmic pressure, but the responsible physical mechanisms remain unresolved. Rather than simply asking whether knockout cells change volume, the project will determine which component of the cellular hydraulic system is altered.

The student will receive interdisciplinary training in advanced quantitative microscopy, biophysics, mammalian cell culture, molecular biology and mathematical modelling.

The project is based at the recently opened Institute for Regeneration and Repair at the University of Edinburgh.

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP). Detailed guidance on the application process, and the EASTBIO Application and Reference Forms can be found at How to Apply | Biology.

http://www.ed.ac.uk/regeneration-repair

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership (DTP). Detailed guidance on the application process, and the EASTBIO Application and Reference Forms can be found at 

https://www.findaphd.com/phds/project/eastbio-decoding-volume-regulation-across-timescales-with-ultrafast-imaging-and-mechanistic-modelling/?p199774

This is a competitive PhD program. Candidate will be selected by the EastBio commitee (not by the project supervisor) on the basis of their CV and performance at the interview.