This week’s featured PhD…

 

Alex Smith, PhD Student
University of Manchester

 

Who are you?

Untitled

Hello! My name is Alex Smith and I am a 3rd year PhD student at the University of Manchester, UK.

My research is all about better understanding how cells communicate with each other and how the same message can be interpreted in different ways.

 

What are you researching?

Consider human development from embryo to adult. How do cells know which cell type to become and when? And how is the complex process of making a human so reproducible?

To transform from a single fertilised embryo into a human containing roughly 35-40 trillion cells requires a lot of cell-to-cell communication. During development and throughout adult life cells are able to communicate to each other by sending and receiving signals between each other. They tell each other when to divide, when to change cell type and even when to commit suicide (termed apoptosis). The whole process from receiving an informational signal to translating that to a meaningful outcome is termed a signalling pathway.

There are many core signalling pathways required for cells to function normally, but my research focuses on just one; the Notch pathway. The Notch pathway is characterised by the membrane receptor protein Notch, which was first identified in the fruit fly (Drosophila melanogaster) where mutated Notch produces wings with notches.

In short, I’m trying to better understand how the same message i.e. Notch activation can be processed differently by the same cell and the consequences of this in terms of disease.

 

Why study Notch signalling?

Aberrant Notch signalling has been linked to many different cancers. In addition mutated Notch causes other rarer hereditary diseases such as CADASIL. Despite this, there is still much to be learnt about how Notch signalling really works. A better understanding of normal Notch signalling will help understand why things go wrong when Notch causes disease.

At the moment, one route of Notch activation is very well understood but there are other routes which are much less understood. Imagine it as though you are travelling from point A to point B and the most obvious and direct route is to take the highway. But there are likely to be less obvious, smaller roads you could take to get you to the same place. These smaller routes may take longer, but they would be ideal if the highway was closed for some unforeseen reason. You’d still be able to get to your destination. The ‘highway route’ of notch signalling is known in very high detail, but it’s the smaller, alternative routes that are much less well characterised. Ultimately, a better understanding of these smaller routes may provide a strategy for developing better therapeutics for Notch-related diseases i.e. providing a diversion when there’s a block in the road.

 

What do you hope to find?     

There are many questions still left unanswered in the Notch field. I hope to address just a few select questions:

  • How long does it take for Notch to travel down each of the separate routes?
  • Which parts, if any, of the Notch protein control the choice of activation route taken?
  • Do CADASIL mutations bias the route of Notch activation or perhaps slow down the whole process?

 

And what then….?

Hopefully, by better understanding how Notch is activated by the different routes and what influences which route is taken, this will inform how Notch causes diseases such as cancer and CADASIL.

Understanding how cellular communication is compromised by aberrant Notch will hopefully shed light on some new drug targets for Notch-related diseases. That’s the goal!

 

Thank you for reading! Please leave comments if you would like to find out more. Alternatively, the review below details what is known about the less understood (endocytic) routes of Notch activation:

https://www.ncbi.nlm.nih.gov/pubmed/22285298

 

 

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