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Precision Medicine DTP - Harnessing plasticity to repair spinal cord injury


Project Description

Background

After a spinal cord injury in the zebrafish, lost neurons are replaced and axonal connections re-established (Tsarouchas et al., 2018). The Becker group (Edinburgh) have recently shown that after injury in zebrafish, a specific new neuron type is being generated from spinal stem cells (Ohnmacht et al., 2016). These neurons express reporter genes for motor neurons (e.g. hb9), but send an axon to grow laterally to reconnect the spinal cord (see figure below). Such neurons are never seen in uninjured animals. Plasticity of neurons and axonal connections, “patching” a spinal injury rather than “re-creating” exactly what was lost is an exciting possibility to regain function. Recent evidence shows indication for plasticity in mammalian spinal cord and transplanted neurons can integrate into spinal circuitry in rats and monkeys.

We hypothesise that in fish, the newly generated neuronal cell type contributes to functional recovery, by acting as an endogenous relay neuron. This may be similar to transplanted neurons applied in therapeutic approaches in the mammalian spinal cord.

Aims

In this collaborative PhD project between the Becker group (Edinburgh) and the El Manira group (Karolinska Institutet), we aim to elucidate the neurotransmitter identity of the newly born neurons and to determine how they are integrated into the regenerated neural network. Electrophysiology on the regenerated network will enable us to determine network changes at unprecedented resolution (Song et al., 2016 and 2018).

For an unbiased approach, the student will determine expression profiles of the new-born and pre-existing neurons from spinal injury sites in zebrafish. The resulting profiles will be analysed for changes in the expression neurotransmission-associated genes and these will be functionally analysed using agonists and antagonists of neurotransmitter receptors and CRISPR/cas9 mediated gene mutation, which is well established in our group.

Hence, this project will identify how increased plasticity through new neurons in a spinal lesion site in zebrafish can lead to repair of function and thus provide targets for future therapeutic approaches in mammalian systems to improve regenerative outcome.

Training Outcomes

The student will be trained in complex cloning techniques, in vivo perturbations and electrophysiological analyses using the zebrafish system, confocal imaging techniques and bioinformatics approaches applied to systems biology. This addresses the MRC key priority “Quantitative Skills” as applied to transcriptomics.

This MRC programme is joint between the Universities of Edinburgh and Glasgow. You will be registered at the host institution of the primary supervisor detailed in your project selection.

All applications should be made via the University of Edinburgh, irrespective of project location. For those applying to a University of Glasgow project, your application along with any supporting documents will be shared with University of Glasgow.
http://www.ed.ac.uk/studying/postgraduate/degrees/index.php?r=site/view&id=919

Please note, you must apply to one of the projects and you must contact the primary supervisor prior to making your application. Additional information on the application process is available from the link above.

For more information about Precision Medicine visit:
http://www.ed.ac.uk/usher/precision-medicine

Funding Notes

Start: September 2020

Qualifications criteria: Applicants applying for a MRC DTP in Precision Medicine studentship must have obtained, or will soon obtain, a first or upper-second class UK honours degree or equivalent non-UK qualification, in an appropriate science/technology area.
Residence criteria: The MRC DTP in Precision Medicine grant provides tuition fees and stipend of at least £15,009 (RCUK rate 2019/20) for UK and EU nationals that meet all required eligibility criteria.

Full eligibility details are available: View Website

Enquiries regarding programme:

References

References

Ohnmacht J, Yang Y, Maurer GW, Barreiro-Iglesias A, Tsarouchas TM, Wehner D, Sieger D, Becker CG, Becker T (2016). Spinal Motor Neurons are Regenerated after Mechanical Lesion and Genetic Ablation in Larval Zebrafish. Development 143:1464-1474

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 (2018) Dynamic control of proinflammatory cytokines Il-1β and Tnf-α by macrophages is necessary for functional spinal cord regeneration in zebrafish, Nature Communications 7;9(1):4670

Song J, Dahlberg E, El Manira A. (2018) V2a interneuron diversity tailors spinal circuit organization to control the vigor of locomotor movements. Nature Communications 9(1):3370.

Song J, Ampatzis K, Björnfors ER, El Manira A. (2016) Motor neurons control locomotor circuit function retrogradely via gap junctions. Nature 529(7586):399-402.

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