Back to search results

PhD Studentship: The impact of altered axonal transport in novel humanised models of motor neuron disease

UCL - University College London - Queen Square Institute of Neurology

Qualification Type: PhD
Location: London
Funding for: UK Students
Funding amount: Fully funded with a stipend and tuition fees paid to UK level
Hours: Full Time
Placed On: 3rd February 2023
Closes: 10th April 2023

Project Title: The impact of altered axonal transport in novel humanised models of motor neuron disease

The molecular mechanisms causing neuronal death in amyotrophic lateral sclerosis (ALS), a major form of motor neuron disease, are poorly understood. Two key consequences of our incomplete understanding of ALS pathogenesis are the lack of effective treatments for this human disorder and the need for a step-change in strategies to fight the disease.

In work leading to this proposal, we uncovered alterations in the transport of several organelles in the axons of motor neurons at pre-symptomatic stages of ALS pathogenesis, suggesting that these impairments play a causative role in disease onset and progression [1, 2]. Crucially, we identified distinct classes of molecules able to restore axonal transport to physiological levels at early symptomatic stages of disease, thus demonstrating that these pathological changes are fully reversible and may be used in future therapies targeting motor neuron disease [3-5].

In this PhD proposal, novel mouse models expressing ALS mutants of human TDP43 and FUS at endogenous levels will be used to further investigate aberrant axonal transport mechanisms. These mice will also be used to explore whether p38 MAPKalpha [3], IGF1R [4] and RET [5] inhibition, together with other small molecules currently being tested in the laboratory, are able to restore physiological rates of transport, therefore constituting an effective therapeutic strategy to treat ALS.

The translational potential of these results will be tested using human iPSC-derived motor neurons carrying the same ALS mutations as those assessed in mice. The PhD student will monitor axonal transport in these human motor neurons and examine whether promising compounds rescue the identified transport impairments. Furthermore, these human motor neurons will be used to analyse molecular changes in the composition of key axonal organelles associated with the observed axonal transport deficits.

This combined approach will allow us to test the hypothesis that counteracting axonal transport deficits represents a novel, effective therapeutic strategy towards treating ALS.

The candidate:

Candidates should be creative and self-motivated with an interest in neuronal cell biology and the translation of basic discoveries in therapies for human neurological conditions. By the start of their appointment, applicants should have obtained a degree in neuroscience or biomedical science (or equivalent) and not be in possession of a PhD.

The selected candidate will be supervised, supported, and mentored by Prof. Giampietro (Gipi) Schiavo and Dr. James Sleigh at UCL. They will join a dynamic, friendly, yet driven research group at the Queen Square Institute of Neurology. Please do not hesitate to contact Prof. Schiavo for more information at giampietro.schiavo@ucl.ac.uk.

References:

[1] Sleigh JN, Rossor AM, et al. Nat Rev Neurol. 2019; 15:691-703.

[2] Tosolini AP, Sleigh JN et al. Acta Neuropath Comm. 2022; 10:121.

[3] Gibbs KL, Kalmar B, et al. Cell Death Dis. 2018; 9:596.

[4] Fellows AD, Rhymes ER, et al. EMBO Rep. 2020; 21:e49129.

[5] Rhymes ER, Tosolini AP, et al. Cell Death Dis. 2022; 13:584

We value your feedback on the quality of our adverts. If you have a comment to make about the overall quality of this advert, or its categorisation then please send us your feedback
Advert information

Type / Role:

Subject Area(s):

Location(s):

PhD tools
 

PhD Alert Created

Job Alert Created

Your PhD alert has been successfully created for this search.

Your job alert has been successfully created for this search.

Ok Ok

PhD Alert Created

Job Alert Created

Your PhD alert has been successfully created for this search.

Your job alert has been successfully created for this search.

Manage your job alerts Manage your job alerts

Account Verification Missing

In order to create multiple job alerts, you must first verify your email address to complete your account creation

Request verification email Request verification email

jobs.ac.uk Account Required

In order to create multiple alerts, you must create a jobs.ac.uk jobseeker account

Create Account Create Account

Alert Creation Failed

Unfortunately, your account is currently blocked. Please login to unblock your account.

Email Address Blocked

We received a delivery failure message when attempting to send you an email and therefore your email address has been blocked. You will not receive job alerts until your email address is unblocked. To do so, please choose from one of the two options below.

Max Alerts Reached

A maximum of 5 Job Alerts can be created against your account. Please remove an existing alert in order to create this new Job Alert

Manage your job alerts Manage your job alerts

Creation Failed

Unfortunately, your alert was not created at this time. Please try again.

Ok Ok

Create PhD Alert

Create Job Alert

When you create this PhD alert we will email you a selection of PhDs matching your criteria.When you create this job alert we will email you a selection of jobs matching your criteria. Our Terms and Conditions and Privacy Policy apply to this service. Any personal data you provide in setting up this alert is processed in accordance with our Privacy Notice

Create PhD Alert

Create Job Alert

When you create this PhD alert we will email you a selection of PhDs matching your criteria.When you create this job alert we will email you a selection of jobs matching your criteria. Our Terms and Conditions and Privacy Policy apply to this service. Any personal data you provide in setting up this alert is processed in accordance with our Privacy Notice

 
 
 
More PhDs from UCL

Show all PhDs for this organisation …

More PhDs like this
Join in and follow us

Browser Upgrade Recommended

jobs.ac.uk has been optimised for the latest browsers.

For the best user experience, we recommend viewing jobs.ac.uk on one of the following:

Google Chrome Firefox Microsoft Edge