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Understanding intracellular calcium dynamics in human Parkinson’s patient stem cell neurons


   Department of Physiology, Anatomy & Genetics

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  Prof R Wade-Martins, Dr Charmaine Lang, Ms Maria Claudia Caiazza  No more applications being accepted  Funded PhD Project (UK Students Only)

About the Project

Project’s Aim

Parkinson’s disease is the second most common neurodegenerative disease, affecting over 6 million people worldwide, a number which is constantly increasing with population aging. Although we know that the main cells lost are dopamine neurons in the midbrain, Parkinson’s still lacks an effective disease modifying cure. As a result, there is in increasing interest in studying early disease mechanisms, with the ultimate goal of targeting cell biology pathways to slow, halt or reverse the progress of the disease.

In order to study pathological events occurring at early stages of Parkinson’s, we use models that can recapitulate early stages of the disease. For this reason, the Oxford Parkinson’s Disease Centre (OPDC; www.opdc.ox.ac.uk) has generated over 200 induced-pluripotent stem cell (iPSC) lines from patients with genetic and sporadic forms of Parkinson’s, as well as age-matched controls. These lines are differentiated into highly physiological midbrain dopaminergic neuronsthe very same neurons that degenerate in Parkinson’s- with the goal of understanding mechanisms of disease onset and progression.

The degeneration of midbrain dopaminergic neurons in Parkinson’s has been associated with altered function of the endoplasmic reticulum and mitochondria. These two organelles are the main calcium stores in the cell, relying on calcium for their correct function. Therefore, we believe that altered dynamics of calcium biology within and between these organelles may be linked to the specific vulnerability of dopaminergic neurons in the disease.

In this project, the new student will study calcium dynamics in the cell body and in the axons of iPSC-derived dopamine neurons from Parkinson’s patients compared to controls. We will examine the function and dysfunction of calcium signalling in and between the endoplasmic reticulum and mitochondria in iPSC-derived neurons from different genetic backgrounds, and then expand the work to look at the dynamics of calcium signalling between the plasma membrane and intracellular organelles. For this project, the new student will maintain iPSCs, differentiate them into dopaminergic neurons, employ cutting-edge calcium imaging techniques, high-content imaging and a broad range of cell and molecule biology techniques to study neuronal biology.

Training

The new student will receive direct training from members of the laboratory on how to grow iPSCs and differentiate them into dopaminergic neurons. The new student will also be fullytrained in calcium imaging techniques, high-content imaging and a wide range of laboratory techniques in cellular neuroscience.

The new student will attend regular seminars at the Oxford Parkinson’s Disease Centre and at the Department of Physiology Anatomy and Genetics.

The new student will be required to present their work regularly in laboratory meetings.

How to Apply

Applications must be submitted on the University website by 3rd December 2021 at noon GMT. Information on how to apply can be found following this link.

Applications should be made to the program: DPhil in Physiology, Anatomy and Genetics, course code RD_PYAG1.

As detailed in the on-line application process, applicants will be required to write a research proposal discussing the use of iPSC-derived dopamine neurons to study aspects of cell biology relevant to Parkinson’s, such as organelle function and calcium dynamics. 


Funding Notes

The scholarship will be funded by a graduate scholarship funded by the Pitts-Tucker Studentship, and held at Christ Church College, Oxford. The scholarship will cover living costs and fees at home rate (includes UK nationals or EU nationals with indefinite leave to remain or with settled or pre-settled status granted under the EU Settlement Scheme that meet the residence criteria, for further information follow this link: https://www.ox.ac.uk/admissions/undergraduate/fees-and-funding/tuition-fees/fee-status). Funding is available for three years, with potential to extend for a fourth year.

References

Lang, C., Campbell, K. R., Ryan, B. J., Carling, P., Attar, M., Vowles, J., Perestenko, O. V., Bowden, R., Baig, F., Kasten, M., Hu, M. T., Cowley, S. A., Webber, C., & Wade-Martins, R. (2019). SingleCell Sequencing of iPSC-Dopamine Neurons Reconstructs Disease Progression and Identifies HDAC4 as a Regulator of Parkinson Cell Phenotypes. Cell stem cell, 24(1), 93–106.e6.
https://doi.org/10.1016/j.stem.2018.10.023
Fernandes, H. J., Hartfield, E. M., Christian, H. C., Emmanoulidou, E., Zheng, Y., Booth, H., Bogetofte, H., Lang, C., Ryan, B. J., Sardi, S. P., Badger, J., Vowles, J., Evetts, S., Tofaris, G. K., Vekrellis, K., Talbot, K., Hu, M. T., James, W., Cowley, S. A., & Wade-Martins, R. (2016). ER Stress and Autophagic Perturbations Lead to Elevated Extracellular α-Synuclein in GBA-N370S Parkinson's iPSC-Derived Dopamine Neurons. Stem cell reports, 6(3), 342–356.
https://doi.org/10.1016/j.stemcr.2016.01.013
Zambon, F., Cherubini, M., Fernandes, H., Lang, C., Ryan, B. J., Volpato, V., Bengoa-Vergniory, N., Vingill, S., Attar, M., Booth, H., Haenseler, W., Vowles, J., Bowden, R., Webber, C., Cowley, S. A., & Wade-Martins, R. (2019). Cellular α-synuclein pathology is associated with bioenergetic dysfunction in Parkinson's iPSC-derived dopamine neurons. Human molecular genetics, 28(12), 2001–2013.
https://doi.org/10.1093/hmg/ddz038
Hartfield, E. M., Yamasaki-Mann, M., Ribeiro Fernandes, H. J., Vowles, J., James, W. S., Cowley, S. A., & Wade-Martins, R. (2014). Physiological characterisation of human iPS-derived dopaminergic neurons. PloS one, 9(2), e87388.
https://doi.org/10.1371/journal.pone.0087388
Caiazza, M. C., Lang, C., & Wade-Martins, R. (2020). What we can learn from iPSC-derived cellular models of Parkinson's disease. Progress in brain research, 252, 3–25.
https://doi.org/10.1016/bs.pbr.2019.11.002
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