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Investigating the role of the mechanosensor channel Piezo1 in human disease

  • Full or part time
  • Application Deadline
    Wednesday, January 23, 2019
  • Self-Funded PhD Students Only
    Self-Funded PhD Students Only

Project Description

Piezo proteins are ion channels that are gated by mechanical stimuli like stretch or shear stress. In mammalians there are two Piezo isoforms (Piezo1 and Piezo2) with largely different expression pattern. Over 25 mutations in Piezo1 have been identified in several human disorders, for example mutations are associated with dehydrated hereditary xerocytosis (caused by excess calcium influx into red blood cells) or congenital lymphatic dysplasia. Piezo proteins have also been implicated in hypertension and in the progression of several cancers. Mechanosensing in cancer tissue is an important new research avenue bearing potential new treatment strategies. The importance of Piezo channels comes from the fact that they are acting as mechanosensors sensing mechanical stimuli and translating these stimuli into biochemical signals (like a calcium influx into cells). Piezo channels are synthesised in the endoplasmic reticulum, however little is known how Piezo proteins are reaching its different membrane compartments and how this is regulated. It is well accepted that membrane trafficking is an integral part of signalling for many membrane proteins. This project will investigate membrane trafficking routes of Piezo1 and how this contributes to mechanosensing and in case of human diseases how this contributes to the patho-mechanism. We will focus here in particular on various cancer models (breast cancer and colon cancer in particular).

Science Graduate School
As a PhD student in one of the science departments at the University of Sheffield, you’ll be part of the Science Graduate School. You’ll get access to training opportunities designed to support your career development by helping you gain professional skills that are essential in all areas of science. You’ll be able to learn how to recognise good research and research behaviour, improve your communication abilities and experience the breadth of technologies that are used in academia, industry and many related careers. Visit http://www.sheffield.ac.uk/sgs to learn more.
Methods: We will make use of modern CRISPR/Cas9 technology to tag endogenous Piezo1. Using live spinning disc confocal microscopy and total internal reflection microscopy we will monitor the trafficking route of Piezo1.
We will complement our studies with investigations of Piezo1 trafficking in 3D cell culture systems as well as in cells encapsulated in alginate shells to mimic pressure build up in tumors. Finally, we will investigate Piezo1 expression and localisation in human cancer tissues.


Literature:

Wu, J., Lewis, A.H., and Grandl, J. (2017) Touch, Tension, and Transduction-The function and regulation of Piezo ion channels. Trends in Biochemical Sciences, 42, 57-70

Piddini, E. (2017) Epithelial homeostasis: A piezo for the puzzle. Current Biol. , 27, R232-R234.

Coste, B. et al. (2012) Piezo proteins are pore-forming subunits of mechanicaly activated channels. Nature 483, 176-181

Funding Notes

Please note that we have a number of fee scholarships available, please get into contact with Dr. Kai Erdmann in case you would like to know more: View Website

Entry requirements
First class or upper second 2(i) in a relevant subject. To formally apply for a PhD, you must complete the University's application form using the following link: View Website

*All applicants should ensure that both references are uploaded onto their application as a decision will be unable to be made without this information*.

References

https://www.sheffield.ac.uk/bms/research/erdmann

How good is research at University of Sheffield in Biological Sciences?

FTE Category A staff submitted: 44.90

Research output data provided by the Research Excellence Framework (REF)

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