Don't miss our weekly PhD newsletter | Sign up now Don't miss our weekly PhD newsletter | Sign up now

  Development of cellular models of oxygen chemosensitivity


   Nuffield Department of Medicine

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
  Prof Peter Ratcliffe, Prof Tammie Bishop, Dr Emma Hodson  No more applications being accepted  Funded PhD Project (Students Worldwide)

About the Project

At the level of the organism one of the most striking responses to oxygen availability is the control of breathing. Though this has been linked to the function of specialised ‘chemosensitive’ cells in the brain and to arterial chemoreceptors in the carotid body, the means by which the oxygen-sensitive signal is generated and how it relates to cell proliferation and tumorigenesis in this organ is still poorly understood (Bishop and Ratcliffe 2020; Colinas et al. 2023). In part this is because of the lack of a good system to study the process at a molecular level. This project builds on work in this laboratory implicating developmental activation of a specific transcription factor (HIF-2alpha) in specifying the chemosensitive phenotype in chromaffin cells (Eckardt et al. 2021; Prange-Barczynska et al. 2023). Capitalising on this new finding, the aim of this project is to generate chemosensitive cell lines, using cell engineering and transgenesis, which are amenable to biochemical approaches and allow for a fully developed molecular analysis of oxygen chemosensitivity, defining, for example, the exact mode of signal generation and the mode of transduction to the target ion channel.

In the first instance, this will be attempted in HPSCs, where established protocols will be used to programme human PSCs to form sympathoadrenal progenitors (Frith et al. 2018). The ability of forced HIF-2 expression to confer oxygen-sensitive electrophysiological responses in these sympathoadrenal progenitors will be explored using calcium indicators for fluorescence detection of oxygen-sensitive calcium influx. The ability of HIF-2 to confer oxygen chemosensitivity will also be tested in existing available chromaffin and related cell lines.

These studies will be guided by parallel analysis of HIF-2 induced chemosensitivity in transgenic mice that seek to compare and contrast genetic signatures of oxygen chemosensitivity across different tissues and to derive insights into transcriptional and non-transcriptional actions of HIF-2 in the induction of chemosensitivity. Overall the aim is to generate new insights and new reductionist systems for molecular approaches to this vital physiological process. 

Training opportunities: We are seeking an enthusiastic and proactive student to join a world-leading laboratory, working on the sensing and signalling of oxygen levels in cells and reporting to Professors Peter J. Ratcliffe, Tammie Bishop and Emma Hodson. Specific skills they will gain are: creation of transgenic cell lines (including cell culture, maintenance and genetic engineering of cells); in vivo imaging and fluorescence microscopy; biochemical analysis; transgenic mouse research.

Please quote the project ID Ludwig and indicate the course code RD_CM1 in your application. Please use the project details above for your research proposal.

The Ludwig Institute for Cancer Research studentships are for 4 years and provide an annual tax-free stipend of £21,000 and fees at the home or international rates.

For entry requirements and to apply for this project please visit the University of Oxford DPhil in Clinical Medicine pages

Please note that only applicants who apply for a DPhil in Clinical Medicine via the University of Oxford admissions system will be shortlisted for interview.

Enquiries

Catherine King ([Email Address Removed]) – project related enquiries

Alexandra Royer ([Email Address Removed]) – application related enquiries

Do not send your application to these email addresses, only applications submitted visa the University of Oxford admissions system will be considered

Application deadline closes Monday 1st April. Deadline for receipt of references: Friday 5th April.

Biological Sciences (4) Medicine (26)

Funding Notes

The Ludwig Institute for Cancer Research studentships are for 4 years and provide an annual tax-free stipend of £21,000 and fees at the home or international rates.

References

Bishop T, Ratcliffe PJ. 2020. Genetic basis of oxygen sensing in the carotid body: HIF2alpha and an isoform switch in cytochrome c oxidase subunit 4. Sci Signal 13.
Colinas O, Moreno-Dominguez A, Ortega-Saenz P, Lopez-Barneo J. 2023. Constitutive Expression of Hif2alpha Confers Acute O(2) Sensitivity to Carotid Body Glomus Cells. Adv Exp Med Biol 1427: 153-162.
Eckardt L, Prange-Barczynska M, Hodson EJ, Fielding JW, Cheng X, Lima J, Kurlekar S, Douglas G, Ratcliffe PJ, Bishop T. 2021. Developmental role of PHD2 in the pathogenesis of pseudohypoxic pheochromocytoma. Endocr Relat Cancer 28: 757-772.
Frith TJ, Granata I, Wind M, Stout E, Thompson O, Neumann K, Stavish D, Heath PR, Ortmann D, Hackland JO et al. 2018. Human axial progenitors generate trunk neural crest cells in vitro. Elife 7.
Prange-Barczynska M, Jones HA, Sugimoto Y, Cheng X, Lima JDCC, Ratnayaka I, Douglas G, Buckler KJ, Ratcliffe PJ, Bishop T. 2023. Hif-2α programmes oxygen chemosensitivity in chromaffin cells. bioRvix.
Search Suggestions
Search suggestions

Based on your current searches we recommend the following search filters.