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How passive diffusivity in cells can be a function of protein diffusant’s physiochemical properties


Project Description

Precise regulation of protein distribution and dynamics is vital for cellular functions and organization. Defects in protein transport have been implicated in degenerative and neoplastic diseases. Passive diffusion is a general strategy for soluble proteins to transport within the cells which is the movement of molecules from regions of higher concentration to regions of lower concentration without energy expenditure. To compartmentalize soluble proteins, cells compose several diffusion barriers in distinct subcellular sites. These passive permeability diffusion barriers serve as conduits in the boundaries among different subcellular compartments and regulate the movement of soluble molecules across adjacent pools. Dysfunction of diffusion barriers leads to mislocation of proteins and has been known to cause human diseases.

Size, electrostatics, and hydrophobicity are three major factors that determine the intrinsic diffusion behavior of soluble molecules. Previous studies by supervisor Yu-Chun Lin have uncovered how molecular size limits movement through passive permeability barriers. Compared to that of size, how electrostatics and hydrophobicity regulate the dynamics of molecules through the passive permeability barriers remains largely unknown. To address these fundamental questions, we here aim to combine bioinformatics, molecular simulations, chemical biological approaches, and mathematical modelling to quantitatively measure the diffusion behaviours of probes with various electrostatic and hydrophobic properties within cells.

We previously established a chemically inducible diffusion trap (CIDT) for precisely measuring the diffusion coefficient of soluble proteins as well as probing diffusion barrier in cells. Leveraging the CIDT, we have determined diffusion rates of soluble proteins with various sizes through passive permeability barriers in the ciliary pore complex and centrosome. Taking advantage of this, we will apply CIDT to measure the diffusion rates of soluble proteins with various electrostatic and hydrophobic properties within cells.

For this project, it is proposed that the Ph.D. student will stay at NTHU for the first 12-24 months to familiarize themselves with basic bioinformatics and MD simulation techniques to design surface properties of proteins, as well as to acquire basic ability of cell culture, DNA transfection and cell imaging. The student will then join Prof Bearon’s group and the Liverpool Centre for Mathematics in Healthcare in UoL and work on developing a mathematical model which captures the diffusive behaviour of proteins.

This project is part of a 4 year Dual PhD degree programme between the National Tsing Hua University (NTHU) in Taiwan and the University of Liverpool in England. As Part of the NTHU-UoL Dual PhD Award students are in the unique position of being able to gain 2 PhD awards at the end of their degree from two internationally recognised world leading Universities. As well as benefiting from a rich cultural experience, Students can draw on large scale national facilities of both countries and create a worldwide network of contacts across 2 continents.

All of the projects undertaken on the Dual PhD are aimed at working towards the UN’s Global Goals for Sustainable Development. In 2015 World leaders agreed to 17 goals for a better world by 2030. These goals are aimed at ending poverty, fighting inequality and stopping climate change. This project is specifically targeted at Goal 9 – to build resilient infrastructure, promote inclusive and sustainable industrialisation and foster innovation.

To apply for this opportunity, please visit: https://www.liverpool.ac.uk/study/postgraduate-research/how-to-apply/
When applying please ensure you Quote the supervisor & project title you wish to apply for and note ‘NTHU-UoL Dual Scholarship’ when asked for details of how plan to finance your studies.

Name and email address to direct enquiries to:

For academic enquires please contact Rachel Bearon () or Yu-Chun Lin ()

For enquires on the application process or to find out more about the Dual programme please contact Shirley Farrell

Funding Notes

Both the University of Liverpool and NTHU have agreed to waive the tuition fees for the duration of the project and stipend of TWD 11,000 TWD Per/Month will be provided as a contribution to living costs .

References

Lin, Y.-C., Phua, S. C., Lin, B. & Inoue, T. Visualizing molecular diffusion through passive permeability barriers in cells: conventional and novel approaches. Curr. Opin. Chem. Biol. 17, 663–671 (2013).
Lin, Y.-C. et al. Chemically inducible diffusion trap at cilia reveals molecular sieve-like barrier. Nat. Chem. Biol. 9, 437–443 (2013).
Duchesne, L. et al. Transport of Fibroblast Growth Factor 2 in the Pericellular Matrix Is Controlled by the Spatial Distribution of Its Binding Sites in Heparan Sulfate. PLoS Biol. 10(7) (2012)

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