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Understanding how extracellular vesicles influence inflammation during tissue regeneration in zebrafish


   School of Physiology, Pharmacology & Neuroscience

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  Dr R Richardson  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

Supervisors: Dr Beck Richardson, University of Bristol and Professor Aled Clayton, University of Cardiff

Summary: Zebrafish have a remarkable ability to regenerate damaged tissues. Tissue repair and regeneration requires communication between multiple different cell types including immune cells, fibroblasts and endothelial cells. Extracellular vesicles (EVs) deliver molecular messages between cells and our data suggests they promote regeneration. This project will determine how EVs might be harnessed to facilitate optimal repair of damaged tissues via influencing inflammation.

Description: Small (30-1000nm) lipid bound extracellular vesicles (EVs) are showing promise as biomarkers and potential therapeutic avenues for multiple diseases including cancer and cardiovascular disease. EVs act as protective vehicles for molecular messages and facilitate communication between cells across extracellular space. EV numbers are elevated following a myocardial infarction and it has been suggested that they can play roles in immunomodulation and neovascularisation during repair (1,2). However, due to the complexity of labelling and tracking these small vesicles there is much to be learnt about EV function in vivo. A previous PhD student in the lab has established a zebrafish model that allows us to identify and isolate endogenous, cell type specific EVs, revealing transfer between cardiovascular cell types and providing the unique opportunity to determine EV function during endogenous regeneration (3). Proteomics of cardiac EVs extracted after injury reveals enrichment of inflammatory and wound healing mediator cargos (including complement proteins, granulin and fibronectin), both early after injury and at the onset of regeneration (unpublished data). This preliminary data suggests that EVs may play a role in modulating inflammatory cells and pathways, processes we have previously shown to be important for cardiac regeneration (4). The overall aim of this project is to further understand the role of this transfer of EV cargos during cardiac repair and regeneration. We hypothesise that cargo transfer to immune cells increases after injury and can have immunomodulatory effects, promoting regeneration. This project will provide excellent training opportunities to develop in vivo skills in a regenerative model, flow cytometry, molecular and ‘omics analyses of tissue samples as well as sophisticated confocal and super resolution microscopy.

Objectives: 1 – Prep period and first 3 months of project. Perform comparative analyses with data from mouse (5) and human (6) cardiac EVs to identify which is the most promising regenerationassociated cargo (Opportunity for the student to steer the project). 2 – Year 1. Determine the cell types producing and receiving these cargo carrying EVs via flow cytometry and imaging of the heart. Our proteomics data is from total cardiac EVs but by using our strategy to transgenically label cell types and their EVs (3) we can determine the cells that are sending and receiving these cargos. Candidates we can already assess include neutrophils, macrophages, endothelial cells and cardiomyocytes. 3 – Year 2. Confirm and extend the evaluation of cardiac EV cargo by assessing RNAs carried by EVs with guidance frothe 2nd supervisor and industrial partner. 4 – Years 2-4. Characterise cardiac injury repair and regeneration in zebrafish lacking proteins carried by EVs. For example, complement components (e.g. C3 and C5) are enriched in our proteomics dataset but the role of this inflammatory pathway hasn’t been studied during regeneration. Mutants for these targets can be generated via CRISPR/Cas9 technology (Opportunity for the student to steer the project).

Deadline for applications:

5pm on Wednesday, 2nd November 2022

DO NOT APPLY TO THE UNIVERSITY OF BRISTOL - YOU MUST FIRST SECURE OFFER OF FUNDING FROM THE DTP (SEE BELOW)

For more information about GW4 Biomed Doctoral Training partnership, including how to apply for this studentship, please see https://gw4biomed.ac.uk/doctoral-students/


Funding Notes

A GW4 BioMed2 MRC DTP studentship includes full tuition fees at the UK/Home rate, a stipend at the minimum UKRI rate, a Research & Training Support Grant (RTSG) valued between £2-5k per year and a £300 annual travel and conference grant based on a 4 year, full-time studentship. Part-time study is also available and these funding arrangements will be adjusted pro-rata for part-time studentships. Throughout the duration of the studentship, there will be opportunities to apply to the Flexible Funding Supplement for additional support to engage in high-cost training opportunities.

References

Akbar N, et al., (2017). JCI Insight. 2(17): e93344
Beltrami C, et al., (2017). Mol Ther. 25(3): 679-693.
Scott A, Sueiro Ballesteros L, Bradshaw M, Tsuji C, Power A, Lorriman J, Love J, Paul D, Herman A, Emanueli C, Richardson RJ. (2021)
In Vivo Characterization of Endogenous Cardiovascular Extracellular Vesicles in Larval and Adult Zebrafish. ATVB. 41(9): 2454- 2468
Bevan L, Lim ZW, Venkatesh B, Riley PR, Martin P, Richardson RJ. (2020) Specific macrophage populations promote both cardiac scar deposition and subsequent resolution in adult zebrafish. Cardiovasc Res. 116(7):1357-1371.
Claridge B, et al., (2021). Proteomics. 21(13-14): e2100026 6. Leitolis A, et al., (2019). Int J Mol Sci. 20(6):1279

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