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Using modelling and C. elegans to target the molecular mechanisms governing Ca2+-linked cognitive decline


College of Medicine and Veterinary Medicine

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Dr Melanie Stefan , Dr E Busch No more applications being accepted Competition Funded PhD Project (Students Worldwide)

About the Project

Deanery of Biomedical Sciences

As we age, our cognitive abilities decline. Among the first to go is the ability to learn new things. Increasing evidence implicates Ca2+ signalling, which is normally required for the plasticity and functional stability of neurons. Ca2+ becomes chronically elevated in ageing neurons, impairing neural plasticity and increasing the risk of neurodegeneration. Understanding the underlying mechanisms is critical to developing novel therapies and ensuring health across the lifespan.
We have established Caenorhabditis elegans as a powerful model to study the mechanisms underpinning calcium signalling and functional decline in neurons. C. elegans responds to ambient oxygen concentration in a way that is dependent on prior experience. In O2-sensing neurons, oxygen elicits a sustained Ca2+ response. Tantalisingly, we find that chronic high ambient O2 results in chronically elevated Ca2+ and a loss of the neurons’ ability to learn new information. This change involves genes controlling Ca2+ homeostasis.

In this project, we aim to better understand the pathways that underlie Ca2+-induced cognitive decline using both computational models and in vivo analyses in C. elegans.

Specific Aims:
1. Create a computational model of Ca2+ signalling in C. elegans O2-sensing neurons, based on experimental data
2. Characterise key pathways governing the decline of neural plasticity with age and chronically elevated Ca2+
3. Understand how these pathways interact to elicit a decline of neural plasticity by making predictions in silico and testing them in vivo.

You will build on an existing chemical kinetic model of calcium signalling in C. elegans neurons, and use this together with transcriptomics data to build computational models of neuronal plasticity in neurons of different ages and oxygen exposures. You can then run simulations to dissect the effects of environmental changes, mutations or pharmacological interventions.

Our data shows that downstream of Ca2+, three highly conserved pathways (calcineurin, mTOR and AMPK) are invovled in the decline of plasticity. You will implement each pathway in the model and run simulations to quantify their contribution to the Ca2+ response under varying conditions. You will use the model to generate hypotheses about how these pathways (inter)act in plasticity and aging, and then test these hypotheses in vivo by targeting pathway components and conducting plasticity assays.

The pathways regulated by Ca2+ signalling are highly conserved in evolution, and we anticipate that the physiological mechanisms we will identify are applicable to humans.

Training outcomes
You will gain multidisciplinary experience by sharing your time between a computational biology group (Stefan) and a C. elegans lab (Busch), and develop skills around computational modelling, functional neural and behavioural assays, genetics and transcriptomics.

References

- Li Q, … Stefan MI and Busch KE (2020) High neural activity accelerates the decline of cognitive plasticity with age in C. elegans. eLife, under revision.
- Li L, Stefan MI, Le Novère, N (2012) Calcium Input Frequency, Duration and Amplitude Differentially Modulate the Relative Activation of Calcineurin and CaMKII. PLoS One 7, e43810.
- Busch KE et al. (2012) Tonic signaling from O₂ sensors sets neural circuit activity
and behavioral state. Nat Neurosci. 15, 581-591.

This 4 year PhD project is part of a competition funded by EASTBIO BBSRC Doctoral Training Partnership. This opportunity is open to UK and international students and provides funding to cover stipend and UK level tuition fees. The UoE covers the difference between home and international fees. There is a cap on the number of international students the DTP can recruit so it is important to know in which fees status category applicants fall under when applying.

Refer to UKRI website and Annex B of the UKRI Training Grant Terms and Conditions for full eligibility criteria.


Funding Notes

Application Procedure
Download application and reference forms from http://www.eastscotbiodtp.ac.uk/how-apply-0

Completed application form along with your supporting documents should be sent to our PGR student team at [Email Address Removed] by 6th January 2021.

References: Please send the reference request form to two referees. Completed references for this project should also be returned to [Email Address Removed] by the closing date: 6th January 2021.

It is your responsibility to ensure that references are provided by the specified deadline.

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