About the Project
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. The injuries in the SC can result from trauma such as falls and road traffic injuries or non-traumatic causes like tumors 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). Due to the lack of understanding of how SC recovers following injury there are no specific treatments available to repair traumatic or non-traumatic SCI. Therefore, there is a need to understand the mechanisms underlying this process to improve therapies.
Zebrafish is a powerful, tractable and robust animal model able to achieve functional regeneration following SCI. 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 SC stroke to elucidate the signals and mechanisms leading to spinal stroke recovery.
In this project you will:
(1) Utilise transgenic fluorescent reporter zebrafish lines to study the impact of bleeding on SC degeneration and regeneration.
(2) Induce haemorrhage in the SC, using laser ablation approach, to measure cellular outcomes
(3) Utilise the transgenic lines to assess dynamic cellular response to SC bleeding in real time
(4) Perform high through-put live imaging to observe neuronal stem-cells, neuronal subtypes, blood vessels, erythrocytes and immune cells
(5) zebrafish larval swimming assays to determine the effects of SC stroke on locomotion
(6) use pharmacological and genetic intervention to manipulate cellular response upon SC stroke
The intended project outcome is the development of a new animal model of SC stroke which can be further utilised to study disease mechanisms, regenerative processes and drug screening to identify potential therapeutic candidates.
Funding Notes
Applications are invited from self-funded students. This project has a Band 3 fee. Details of our different fee bands can be found on our website View Website
References
2. Shaban A, Moritani T, Al Kasab S, Sheharyar A, Limaye KS, Adams HP Jr. Spinal Cord Hemorrhage. J Stroke Cerebrovasc Dis. 2018 Jun;27(6):1435-1446. doi: 10.1016/j.jstrokecerebrovasdis.2018.02.014.
3. X. Soto*, J. Burton, C. Manning, T. Minchington, R. Lea, J. Lee, J. Kursawe, M. Rattray, N. Papalopulu*. (2022). “Sequential and Additive Expression of miR-9 precursors Control Timing of Neurogenesis”. Development. https://doi.org/10.1242/dev.200474
4. Crilly S, Parry-Jones A, Wang X, Selley JN, Cook J, Tapia VS, Anderson CS, Allan SM, Kasher PR. Zebrafish drug screening identifies candidate therapies for neuroprotection after spontaneous intracerebral haemorrhage. Dis Model Mech. 2022 Mar 1;15(3):dmm049227. doi: 10.1242/dmm.049227.
5. Tsarouchas TM, Wehner D, Cavone L, Munir T, Keatinge M, Lambertus M, Underhill A, Barrett T, Kassapis E, Ogryzko N, Feng Y, van Ham TJ, Becker T, Becker CG. Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages in zebrafish spinal cord regeneration. Nat Commun. 2018 Nov 7;9(1):4670. doi: 10.1038/s41467-018-07036-w.
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