MRC-DTP PhD position, Understand spinal cord injuries: Developing a zebrafish model of spinal stroke

Dr. Ximena Soto ( https://research.manchester.ac.uk/en/persons/ximena.soto ) (https://orcid.org/0000-0003-2680-1837 ) is looking for a PhD student enthusiastic and keen on using Zebrafish to elucidate the signals and mechanisms involved in spinal cord regeneration!.

The Soto lab focuses in understanding traumatic and non-traumatic spinal cord injuries, functional importance of dynamic gene expression underlying spinal cord regeneration (SCR) and the mechanism by which microRNAs regulate it using Zebrafish as research organism.

Project description

Spinal cord (SC) injuries (SCI) are devastating affecting at least 4400 people per year in the UK. It carries substantial individual and societal costs with most SCI sufferers experiencing chronic pain. Due to the lack of understanding of how SC recovers following injury no specific treatments are available to repair SCI. Therefore, there is a need to understand the mechanisms underlaying this process to improve therapies for SCI.

The injuries in the SC can result from trauma such as falls and road traffic injuries or non-traumatic causes like tumours and vascular conditions such as spinal strokes. Spinal strokes are rare, but they could be as serious as traumatic SCI. They are caused by disruption of blood supply to the SC due to a spontaneous ischaemic (Zalewski et al, 2019) or haemorrhagic event (Shaban et al, 2018). Symptomatic presentation in patients depends on the location of the infarct but can lead to severe back pain, changes in sensation, incontinence, muscle weakness and paralysis (Vuong et al, 2016).

Zebrafish is a powerful, tractable and robust animal model able to achieve functional regeneration following SCI. Elucidating the signals and mechanisms leading the successful regeneration in this model would generate valuable discoveries to be tested in higher organisms. Taking advantage of its transparency and its amenability to genetic manipulation (Soto et al, 2022) zebrafish offers a powerful approach for studying both vascular (Crilly et al, 2022) and CNS-related diseases (Tsarouchas et al, 2018). The aim of this project is to develop a zebrafish larval model of spinal cord stroke to elucidate signals and mechanisms driving spinal cord regeneration.

In this project, we will utilise transgenic fluorescent reporter zebrafish lines to study the impact of bleeding on SC degeneration and regeneration, in presence or absence of traumatic SCI. Using a laser ablation approach (Liu et al, 2016; O’Brien et al, 2009; Villegas et al, 2012), we will induce haemorrhage around the spinal cord to measure cellular outcomes. The transgenic reporter lines will allow us to use high resolution live imaging to observe spinal neurons, blood vessels, erythrocytes and immune cells, and to visualise the dynamic cellular response to spinal cord bleeding in presence of traumatic SCI in real time. We will also perform zebrafish larval swimming assays to determine the effects of spinal cord stroke on locomotion. We will aim to modify cellular and swimming outcomes through pharmacological and genetic intervention studies.

METHODS AND TRAINING

The PhD project will be based within the Soto lab with co-supervision provided by Kasher and Dorey. The Soto lab will provide training in zebrafish, genome editing (CRISPR-Cas9), transgenesis, advance microscopy techniques and image analysis that will underpin the project. There is extensive expertise in these methods in Soto lab, which is also an expert in the study of dynamic gene expression during brain development and methods to manipulate and study protein dynamic expression. Dr. Kasher focuses on understanding disease mechanisms associated with intracerebral haemorrhage (ICH) – a type of stroke that is caused by spontaneous rupture of blood vessels within the brain using zebrafish and mouse as animal models, as well as in vitro techniques. The Kasher lab will provide training associated to approaches to induce stroke in zebrafish larvae as well as drug intervention studies. Dorey investigates the mechanisms underpinning spinal cord regeneration in Xenopus and focus in unravelling the neurogenic transcriptional trajectory of Neural Progenitor Cells during regeneration. Dorey will provide training in RNA sequencing and data mining. The combined and complementary expertise provided by Soto, Dorey and Kasher labs will equip the student with excellent training opportunity.

In this project you will:

(1) Utilise transgenic fluorescent reporter zebrafish lines to study the impact of bleeding on SC degeneration and regeneration in presence or absence of traumatic SCI.

(2) Utilise the transgenic lines to assess in real time dynamic cellular response during SCR upon SC bleeding

(3) Perform high through-put live imaging to observe neuronal stem-cells, axonal repair, neuronal subtypes, blood vessels, erythrocytes and immune cells

(4) zebrafish larval swimming assays to determine the effects of SC stroke on locomotion

(5) use pharmacological and genetic intervention to manipulate cellular response upon SC stroke

PROJECT INFORMATION

Name

(MRC DTP) Understand spinal cord injuries: Developing a zebrafish model of spinal stroke

Link on FindAPhD

https://www.findaphd.com/phds/project/mrc-dtp-understand-spinal-cord-injuries-developing-a-zebrafish-model-of-spinal-stroke/?p175112

Funding

The appointed candidates will be fully funded for 4 years and the funds will provide for:

• Tuition fees at the standard UKRI rate (OS candidates accepted, up to a maximum quota of 30%, to be managed by the Board)
• Annual stipend at the minimum UKRI rate
• Access to competitive internal DTP funding schemes such as the ‘Annual Flexible Training Supplement’ towards project running costs/consumables, conference/workshop attendance, career development opportunities

Eligibility

Applicants must 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 a relevant discipline.

Before you Apply Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.

How to Apply

To be considered for this project you MUST submit a formal online application form – full details on how to apply can be found on the MRC DTP website https://www.bmh.manchester.ac.uk/study/research/mrc-dtp/

Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team.

Deadline for applications is midnight 15th November 2024