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  The Role of Cell Fusion in Maintaining and Restoring Cerebellar Function


   Bristol Medical School

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  Dr Kevin Kemp  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

The cerebellum plays a critical role in control and coordination of movements in addition to higher-order functions including cognition and emotional processing. Diseases involving the cerebellum occur relatively commonly in children and adults around the world. Injury can occur via numerous mechanisms including genetic disease, stroke, infection, autoimmune disease, and cancer[1]. Loss of Purkinje neurons (PNs), the output from the cerebellar cortex, is a prominent feature of cerebellar damage. PNs are not generated after birth[2], and their loss is characterised by chronic ataxia, impaired muscle coordination, difficulties with speech, swallowing and eye movements.

Stem cell therapies offer potential to restore neuronal function following cerebellar degeneration. Stem cells derived from the bone marrow (BM) can migrate into the brain and merge (fuse) with damaged PNs[2-4] in both humans and rodent models of neurodegenerative disease. By fusing together, BM-derived cells transfer a healthy nuclei to damaged neurons leading to repair and restoration of function [4]. This biological phenomenon offers a promising pathway to overcome the difficulty of replacing injured neurons, but we understand very little about its mechanism. Here we will characterise how and why cell fusion occurs, with the goal of manipulating it as a novel therapeutic approach to treat neurodegeneration.

Aims and objectives

Aims/objectives: The principle aims of this research project will be to determine the role cell fusion has on maintaining cerebellar function in health and disease and to develop therapeutic strategies that harness cell fusion events to boost Purkinje neuron survival. We will identify the factors that promote cell fusion, and the cellular/molecular pathways by which cell fusion restores neuronal health.

Hypothesis: Cell fusion between bone marrow-derived cells and dysfunctional, damaged, or aging Purkinje neurons acts as a natural biological mechanism to maintain cerebellar function and can be upregulated to combat neurodegeneration.

Methodology

By employing models of aging and cerebellar disease, in combination with state-of-the-art transplantation, genetic modification and imaging techniques, we will study cell fusion in the cerebellum between bone marrow-derived cells and Purkinje neurons. We will use in vivo two-photon imaging to perform real time visualisation of cell fusion events in the brain. This will enable us to monitor neuro-immune interactions, during cell fusion events, in the cerebellar cortex. In addition, we will track neuronal activity post-fusion to define the contribution of cell fusion towards synchronicity and rhythmicity of Purkinje neuron firing and cerebellar function. Using genomic and histological techniques, we will characterise the changes to gene and protein expression in fused cells. We will also explore pharmacological approaches to augment cell fusion in the brain by upregulating molecules that promote cell fusion. This study will help to provide novel insights into how neurons are protected in adult life and lead to the development of therapies that will impact on symptoms and long-term disability in people with cerebellar disease.

Supervisors: Kevin Kemp (primary supervisor), Sian Baker, Dr Paul Chadderton, Dr Elisabeth Meyer

How to apply for this project

This project will be based in Bristol Medical School - Translational Health Sciences in the Faculty of Health Sciences at the University of Bristol. Use this information to search for the relevant programme in our online application system.


Biological Sciences (4) Medicine (26)

References

1. Ashizawa, T. and G. Xia, Ataxia. Continuum (Minneap Minn), 2016. 22(4 Movement Disorders): p. 1208-26.
2. Weimann, J.M., et al., Contribution of transplanted bone marrow cells to Purkinje neurons in human adult brains. Proc Natl Acad Sci U S A, 2003. 100(4): p. 2088-93.
3. Kemp, K.C., et al., Purkinje cell injury, structural plasticity and fusion in patients with Friedreich's ataxia. Acta Neuropathol Commun, 2016. 4(1): p. 53.
4. Kemp, K.C., et al., Aberrant cerebellar Purkinje cell function repaired in vivo by fusion with infiltrating bone marrow-derived cells. Acta Neuropathol, 2018. 135(6): p. 907-921.

Where will I study?

 About the Project