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SWBio DTP PhD project - Inferring ion channel mutations from changes in electrical activity of neuronal cells: a top-down quantitative link relating cell function to the molecular properties within the cell membrane


   Department of Physics

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  Prof Alain Nogaret  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

This project is one of a number that are in competition for funding from the South West Biosciences Doctoral Training Partnership (SWBio DTP).

The SWBio DTP is funded by BBSRC and involves a partnership of world-renown universities, research institutes and industry across the South West and Wales. This partnership represents a distinctive group of bioscientists with established international, national and regional networks and widely recognised research excellence. We aim to provide students with outstanding interdisciplinary research training.

Studentships are available for entry in October 2023.

All SWBio DTP projects will follow a structured 4-year PhD programme, combining traditional project-focussed studies with a taught first year which includes directed rotation projects.

Supervisory Team:

Lead supervisor: Prof Alain Nogaret, University of Bath, Department of Physics (email: [Email Address Removed])

Co-supervisors: Dr James Hodge (University of Bristol), Dr Adelina Ilie (University of Bath), Dr Kyle Wedgwood (University of Exeter) and Prof John Brown (University of Exeter)

The Project:

Many neurological diseases such as epilepsy, brain cancer and Alzheimer’s disease originate from mutations in ion channels.  These are pore-forming protein molecules which control the flow of ionic currents across the cell membrane hence the electrical properties of neurons. Bottom-up gene sequencing methods such as transcriptomics and proteomics can identify protein mutations, however they are unable to tell which specific mutations are responsible for changes in electrical activity in the disease state. A top-down quantitative approach is needed to infer ion channel mutations responsible for changes in electrical activity to the exclusion of all others that do not affect electrical function. This is critically important to correctly diagnose channelopathies, improve drug screening, and help design optimal treatment strategies.

The aim of this PhD studentship is to build on the recent advances of the Bath team, to infer the hidden parameters of ion channels from the observation of neuronal oscillations. You will use and adapt powerful computational tools based on data assimilation to extract these parameters by synchronizing multi-channel conductance models to time series recordings of actual neurons. You will first test the computational method on model data to obtain ion channel parameters, reconstruct ionic current dynamics and predict neuron oscillations. You will then analyse electrophysiological time series data measured on epileptic neurons (drosophila), Alzheimer neurons (mice) and healthy control neurons. The computational method will provide complete information on the complement of ion channels of diseased neurons which will be compared healthy neurons. In this way, you will have identified the functionally relevant mutations of Alzheimer and epileptic neurons. Electrophysiological recordings will be obtained in collaboration with partners at the Universities of Bristol and Exeter. Patch clamp recordings of Alzheimer neurons will be recorded on transgenic mice models of Alzheimer’s disease with Exeter partners. Patch clamp recordings epileptic neurons will be recorded of a model of epilepsy in the fruit fly at the University of Bristol. Completed computational models will further predict the behaviour of diseased a healthy neurons to validate the method. The information providing by these models will help neuroscientists design strategies to restore brain function in neurological disease.

Project keywords: Ion channels (Neuroscience), Parameter estimation (Biophysics), Interior point optimization (Mathematics), Multichannel conductance models (Computational modelling)

Candidate Requirements:

Applicants should have obtained, or be about to obtain, a First or Upper Second Class UK Honours degree, or the equivalent qualifications gained outside the UK, in Physics, Mathematics, Natural Science or similar. They should also have an analytical mind and interest in applying the quantitative methods of Physics or Biology. Applicants with a Lower Second Class degree will be considered if they also have Masters degree or have significant relevant non-academic experience.

In addition, due to the strong mathematical component of the taught course in the first year and the quantitative emphasis in our projects, a minimum of a grade B in A-level Maths or an equivalent qualification/experience* is required.

* Physics A-level (grade B and above) or units in your degree with a significant mathematical component, e.g. maths, statistics, bioinformatics.

Applicants must ensure they highlight their Maths background within their application and to upload any supporting evidence.

If English is not your first language, you will need to have achieved Academic IELTS 6.5 overall (with no less than 6.5 in any of the four skills). Find details of other acceptable tests and further information on our website.

Enquiries and Applications:

Informal enquiries are welcomed and should be directed to the lead supervisor.

Formal applications should be submitted on the University of Bath’s online application form for a PhD in Biosciences (Biology & Biochemistry). Note: if you are successful, you will be transferred to the PhD in Physics (SWBio DTP) programme when we issue an offer of study.

When completing the form, please identify your application as being for the SWBio DTP studentship competition in Section 3 Finance (question 2) and quote the project title and lead supervisor’s name in the ‘Your research interests’ section.  You may apply for more than one project within the same application but you should upload a separate (clearly labelled) personal statement for each one, outlining your interest and suitability for that particular project.

See our website for more information about applying for a PhD at Bath.

Equality, Diversity and Inclusion:

We want to support diverse and inclusive work environments. We therefore welcome applications from individuals regardless of their race, ethnicity, sexual orientation, religion, age, gender or disability status.

If you have circumstances that you feel we should be aware of that have affected your educational attainment, then please feel free to tell us about it in your application form. The best way to do this is a short paragraph at the end of your personal statement.


Funding Notes

Candidates may be considered for SWBio DTP studentship tenable for 4 years. Funding covers tuition fees, a stipend (£17,668 p/a in 2022/23) plus an allowance for research/training costs, fieldwork, conference attendance and a 3-month placement. Studentships are open to both Home and International students; however, International applicants should note that funding does NOT cover the cost of a student visa, healthcare surcharge and other costs of moving to the UK. In line with guidance from UK Research and Innovation (UKRI), the number of awards available to International candidates will be limited to 30% of the total.

References

Automatic Construction of Predictive Neuron Models through Large Scale Assimilation of Electrophysiological Data, Alain Nogaret, C. Dan Meliza, Dan Margoliash, Henry Abarbanel, Scientific Reports 6, 32749 (2016)
DOI: 10.1038/srep32749
The Statistical Physics of Data Assimilation and Machine Learning, Henry Abarbanel, Cambridge University Press, 2022

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