Fighting the zombie apocolypse: developing new compounds to counteract senescence in the brain through type-I interferon signalling reduction

Treatment of neurodegenerative disease desperately needs a breakthrough as drugs for current targets, e.g. amyloid in Alzheimer’s Disease, are failing to translate to patients. This lack of translation requires a new approach, with neuroinflammation, particularly its link to cellular senescence, being one of the most promising areas. Senescent cells, where the cell undergoes a number of phenotypic changes and stops dividing, but does not die, are linked to ageing and observed at an increased level in neurodegenerative disease. Unravelling the complex biology around neuroinflammation, cellular senescence and neurodegeneration to design a successful drug discovery programme requires excellent chemical probes, which we currently don’t have. We are developing a range of new type-I interferon (IFN-I) signalling inhibitors within the Madden group at Newcastle, particularly focusing on compounds with novel mechanisms of action compared to widely available competitive Janus kinase (JAK) inhibitors, which struggle due to a lack of selectivity. JAK inhibitors have been shown to reduce cellular senescence, leading us to hypothesise that IFN-I signalling plays a role in cellular senescence as well as neuroinflammation.

This project aims to evaluate and develop these new IFN-I signalling inhibitors as agents which change the function of senescent cells, known as senomorphic agents, to study how they affect brain immune and nerve cell phenotypes. Based at Newcastle University, you will work with other molecular neuroscientists in the group of Dr Kate Madden, collaborating with senescence expert Dr Satomi Miwa. You will also collaborate with Professor Ian Wood at Leeds University, where you will have the opportunity to learn the latest techniques for studying brain immune cell activation and senescence. You will perform chemical synthesis of new IFN-I signalling inhibitors, then test them in a range of cellular assays studying immune activation and cellular senescence. Assay technologies such as high content imaging, cell metabolism studies, flow cytometry and automated liquid handling will be used to profile these chemical tools, supported by excellent facilities within Newcastle.

By the end of this project, you will have developed a broad range of interdisciplinary skills in chemical neuroscience and developed a range of well-defined chemical tools that will be used to interrogate the role of IFN-I signalling in senescence. This will enable us to find new targets for drug discovery aimed at reducing cellular senescence, neuroinflammation and neurodegeneration, taking us a step closer to finding drugs for millions of people worldwide suffering from neurodegenerative disease.

How to Apply:

FURTHER DETAILS AND A GUIDE TO THE FORMAT REQUIRED FOR THE APPLICATION DOCUMENTS IS AVAILABLE AT https://www.ncl.ac.uk/research/transformative-neuroscience/studentship/ . Please read the information there before submitting your application. Applications not meeting these criteria may be rejected.

Applications should be made by emailing [Email Address Removed] with:

• a completed copy of the Application Form. A blank copy of the form can be found at: https://www.ncl.ac.uk/research/transformative-neuroscience/studentship/
• a CV (including contact details of two academic referees).
• a covering letter. This should explain your particular interest in the projects selected, and include any additional information you feel is pertinent to your application
• copies of your degree transcripts and certificates
• a copy of your passport (photo page).
• your English language certificate (IELTS or TOEFL certificate, where applicable)

Informal enquiries may be made to the supervisors.