James Fielding

Highly Commended in Year 2 Graduate Prize

In 2010, at the age of 16, I had the amazing opportunity to work with the Bishop/Ratcliffe group as a part time research assistant, developing my work on hypoxia in the carotid body into a thesis that won Magdalen College's Presidents Prize for Waynflete Studies. Fast forward to 2015 and I was able to return to the lab to start my Dphil under a Ludwig Cancer Research Studentship, shortly after completing my undergraduate degree in Natural Sciences from the University of Cambridge.

My Dphil has continued this early work, focusing on understanding the role played by the HIF (hypoxia-inducible factor) pathway in proliferation and tumorigenesis. Although hypoxia and its regulation by the HIF pathway is strongly associated with cancer, it is remains a major unanswered question within the field whether HIF pathway activation plays an active role in tumor initiation per se or is simply upregulated as a consequence of tumor metabolism. Much of my work has focused on the carotid body, a peripheral chemoreceptor which mediates the body's response to hypoxia and undergoes a marked hyperplasia in response to chronic hypoxia. In my early work, we demonstrated that the carotid body's proliferative response to hypoxia was dependent on HIF-2. This, combined with the 10x fold occurrence of carotid body paragangliomas at altitude, suggested that HIF mediated proliferation may play an active role in tumorigenesis in the carotid body.

In the last two years, I have pursued this hypothesis, first identifying Type I cells as the proliferative population in the carotid body using a novel lineage tracing approach. I then employed a series of transgenic mice to demonstrate that this proliferative response is dependent on HIF-2 and can be induced through HIF-2 stabilization via PHD2 inactivation in Type I cells. Most notably, PHD2 inactivated mice develop phenotypes reminiscent of carotid paraganglioma, suggesting that HIF stabilization may be a key early step in tumorigenesis. Together, these observations provide a paradigm for understanding and modelling the role of HIF in the development of pseudo-hypoxic cancers such as observed in disease of the VHL tumour suppressor.

Conducting my research in the Nuffield Department of Medicine has been an unrivalled experience, in large part due to plentiful support from the department and expert mentoring from my supervisors Tammie Bishop and Peter Ratcliffe, with whom I look forward to working with towards the completion of my thesis.

Publications
Bishop, T., et al., Carotid body hyperplasia and enhanced ventilatory responses to hypoxia in mice with heterozygous deficiency of PHD2. J Physiol, 2013. 591(14): p. 3565-77.

Hodson, E.J., et al., Regulation of ventilatory sensitivity and carotid body proliferation in hypoxia by the PHD2/HIF-2 pathway. J Physiol, 2016. 594(5): p. 1179-95.