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Using antibodies as templates to develop small molecule anti-complement drugs to deliver to Alzheimer’s brain.

   Cardiff School of Medicine

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  Dr Wioleta Zelek, Dr Georgina Menzies, Prof B Paul Morgan  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

The School of Medicine, Dementia Research Institute (DRI) at Cardiff University is delighted to offer a full time three years funded Alzheimer's Society Studentship starting on 3rd October 2022.

Complement is a system of proteins in blood that exists to counter bacterial infections, either by directly killing bacteria or provoking white blood cells to eat them. The direct-killing part of complement system is a protein complex called MAC (membrane attack complex) which bursts bacteria and human cells alike by poking holes in their surfaces like a pinprick in a balloon. Leaking cells cause lots of inflammation, triggering a vicious cycle. Complement induced inflammation drives pathology in many diseases, eg. Multiple Sclerosis, Neuromyelitis Optica, Myasthenia Gravis, Age Macular Degeneration, and Alzheimer’s (AD).

This project will test the idea that inhibiting MAC formation can reduce brain inflammation and subsequent brain degeneration in AD.

You will target MAC in order to block the "hole-punching” activity most harmful to our own cells and the most inflammatory part of complement system, while leaving the white cell-provoking activity of complement intact and available to kill bacteria.

You will generate brain-penetrant MAC-blocking drugs that can stop MAC-driven brain inflammation, providing a novel way of treating AD. You will do this by taking immune molecules called monoclonal antibodies developed in our lab that efficiently block MAC, and define precisely their binding sites on MAC. Based on this information you will design small, brain-penetrant drugs and test them for MAC inhibition and ability to cross the blood-barrier-barrier (BBB) using test-tube models. These studies will provide a proof-of-concept for their use in AD.

You will be offered a technique-rich training encompassing wet-lab (complement assays; brain penetrance assays; protein expression and characterisation) and dry-lab (bioinformatics; computational and mathematical approaches) for modelling proteins-protein interaction; prediction of binding sites and CDRs; drug design.

There will also be wider training provided in research methods, indicative examples are inclusion in a journal club, and training in intellectual property aspects of research. There will also be participation in the seminar/webinar series, conferences and networking events available both in UK-DRI and MEDIC.

You will be part of the Cardiff DRI, an internationally recognised leading neuroscience research centre within the School of Medicine at Cardiff. The DRI Cardiff provides access to unprecedented infrastructure, with world leading research facilities with advanced methodologies for underpinning mechanism of pathology in Alzheimer’s and other dementias. You will be part of a large diverse and inclusive cohort of PhD students (~50) and a very active early career researcher (ECR) network. The student will register in School of Medicine (>160 PhD students) which delivers a comprehensive PGR curriculum with UKPSF benchmarking and focused on student development. The team is very well connected, and this provides multiple opportunities to gain extensive experience and develop effective networks. For example, participating in local ECR seminar series, symposiums, national and international conferences e.g. ARUK, Connectome, Complement UK, International Complement Workshop. 

Entry Requirements  

Applicants should possess a minimum of an upper second class Honours degree, master's degree, or equivalent in a relevant subject. 

Applicants whose first language is not English are normally expected to meet the minimum University requirements (e.g. 6.5 IELTS) 

How to Apply  

This studentship has a start date of October 2022. In order to be considered you must submit a formal application via Cardiff University’s online application service. (To access the system click 'Apply Online' at the bottom of this advert) 

There is a box at the top right of the page labelled ‘Apply’, please ensure you select the correct ‘Qualification’ (Doctor of Philosophy), the correct ‘Mode of Study’ (Full Time) and the correct ‘Start Date’ (October 2022). This will take you to the application portal. 

In order to be considered candidates must submit the following information: 

• Supporting statement 

• CV 

• Qualification certificates 

• References x 2 

• Proof of English language (if applicable) 

Funding Notes

This Alzheimer's Society PhD studentship includes a stipend (£15,000 per year), university PhD fees at UK rates, consumables & equipment, and conference dissemination support.

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