Project Reference: TRG27-IMR-DG1
Project title: The molecular biology of GLUT4 in insulin resistance
Project outline
Every cell must decide when to take glucose out of the blood. In muscle and fat, that decision is made by moving a single protein. GLUT4 is a glucose transporter held inside the cell in a dedicated set of vesicles, and only when insulin arrives are those vesicles delivered to the cell surface. Muscle clears around 80% of the glucose taken up after a meal, and it does so almost entirely through this one trafficking step. It is one of the clearest examples in biology of a hormone signal being converted directly into the movement of a membrane.
Despite decades of work, how that conversion happens is not understood. The field has also assumed that insulin drives the system to its maximum. We wish to challenge this hypothesis.
You will work out how it happens. We will ask three questions:
- It is possible to increase cell surface glut4 above maximum levels?
- What machinery could do this?
- How could this be therapeutically translatable towards diabetes?
You will watch single GLUT4 vesicles moving in living cells using super-resolution microscopy, dissect the machinery with molecular cell biology and gene editing, and determine the structures of the proteins responsible. You will also train and use the AI cell phenotyping pipelines we build in the lab, measuring trafficking behaviour across thousands of cells rather than dozens.
This is fundamental cell biology. However, the project will explain how a cell sets the sensitivity of a hormone response, and how much capacity that response has in reserve.
This project is a collaboration with the lab of Daniel Fazaklerley at the IMS, Cambridge.
Principal Supervisor
Dr David Gershlick
Email address: dg553@cam.ac.uk
Department / Partner Institute: Cambridge Institute for Medical Research (CIMR)
Website: https://www.gershlicklab.com/
BBSRC strategic theme
Understanding the rules of life