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Aiming to elucidate the pathophysiological basis of human neurological disorders from genetic molecular networks to complex neural systems.

  • Full or part time
  • Application Deadline
    Friday, January 11, 2019
  • Competition Funded PhD Project (Students Worldwide)
    Competition Funded PhD Project (Students Worldwide)

Project Description

Aiming to elucidate the pathophysiological basis of human neurological disorders from genetic molecular networks to complex neural systems.

Our lab is interested in developing novel tools, resources and approaches to enable discovery of new therapies for patients with neurological disorders. We use human induced pluripotent stem cell (IPSC) models to generate brain constituent cell types from neurons to microglia to the cerebral vasculature. We then using omics technique such as single cell transcriptomics to identify disease signatures and relate these to cellular disease phenotypes. In order to identify cellular phenotypes we use microscopy, calcium imaging, multi-electrode arrays and patch clamp electrophysiology as well as the usual molecular biology techniques. We have successfully used this approach to find a novel activator of the two potassium channel TRESK, which is now being developed as a pain therapeutic

There are two main areas that we would welcome a new student to undertake research:

The first is on understanding the molecular mechanisms of autism and how gene-environment interaction may affect human cellular phenotypes and drug responses. We have been investigating how loss of function of the gene, TSC2 can alter neural progenitor cell cycle and subsequent cell fate choices leading to greater production of glia. The glial-neuronal imbalance is significantly altered by nutrients in the cell culture media highlighting the important of gene-environment interactions. We believe that the glial-neuronal imbalance then alters neuronal circuit function causing autism and promoting epileptogenesis.

The second area is on the role of brain endothelial cells in the development of dementia. Neurovascular interactions are fundamental to brain function and compromise of the neurovascular unit occurs early in dementia. We have developed a new protocol to generate brain endothelial cells from iPSC and demonstrated it can form an effective blood-brain-barrier. We would now like to investigate how brain endothelial cells generated from Alzheimer’s patients can affect endothelial cell function and how neurovascular interactions may be changed.

The student will be trained in stem cell culture and differentiation. Depending on the project the student would also be trained in omics profiling such as single cell RNA sequencing and epigenetic studies; electrophysiology approaches such multi-electrode arrays and patch-clamp electrophysiology; and functional assays such as calcium imaging. There will also be training on analysis of the data generated by each of these methods.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

All MRC WIMM graduate students are encouraged to participate in the successful mentoring scheme of the Radcliffe Department of Medicine, which is the host department of the MRC WIMM. This mentoring scheme provides an additional possible channel for personal and professional development outside the regular supervisory framework.

Funding Notes

Funding for this project is available through the WIMM Prize Studentship, which offers funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

Applications must be received, including all relevant supporting materials, by Friday 11th January 2019 at 12 noon (midday).

Please visit our website for more information on how to apply.

References

Volpato V, Smith J, Sandor C, Ried JS, Baud A, Handel A, Newey SE, Wessely F, Attar M, Whiteley E, Chintawar S, Verheyen A, Barta T, Lako M, Armstrong L, Muschet C, Artati A, Cusulin C, Christensen K, Patsch C, Sharma E, Nicod J, Brownjohn P, Stubbs V, Heywood WE, Gissen P, De Filippis R, Janssen K, Reinhardt P, Adamski J, Royaux I, Peeters PJ, Terstappen GC, Graf M, Livesey FJ, Akerman CJ, Mills K, Bowden R, Nicholson G, Webber C, Cader MZ, Lakics V. Reproducibility of Molecular Phenotypes after Long-Term Differentiation to Human iPSC-Derived Neurons: A Multi-Site Omics Study. Stem Cell Reports. 2018 Sep 6.

Parkes I, Chintawar S, Cader MZ. Neurovascular dysfunction in dementia – human cellular models and molecular mechanisms. Clinical science 2018; 132(3):399-418.

Haenseler W,.., Cader MZ, et al. A Highly Efficient Human Pluripotent Stem Cell Microglia Model Displays a Neuronal-Co-culture-Specific Expression Profile and Inflammatory Response. Stem Cell Reports. 2017 Jun 6;8(6):1727-1742.

Handel AE,.., Cader MZ. Assessing similarity to primary tissue and cortical layer identity in induced pluripotent stem cell-derived cortical neurons through single-cell transcriptomics. Hum Mol Genet. 2016 Mar 1;25(5):989-1000.

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

Research output data provided by the Research Excellence Framework (REF)

Click here to see the results for all UK universities

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