Regulation of the In Vivo Response to Cardiac Hypoxia – The Role of FIH1

Hypoxia-inducible factors (HIFs) are transcription factors present in all mammalian cells, and play a pivotal role in the molecular response to changes in oxygen availability. Regulation of HIF transcriptional activity is thought to be via 2 mechanisms, the best understood being constant HIF degradation. The second, less well understood mechanism is via activation of co-factors such as iron, via factor inhibiting HIF-1 (FIH1). Little is known about how FIH1 functions in vivo, and the consequences for the intact organism. FIH1 may act in concert with prolyl hydroxylase enzymes to maintain HIF transcriptional activity throughout the physiological range of oxygen concentrations, thus acting as a fine control of the transcriptional response to hypoxia.

This PhD is part of an established research project which is investigating the role of FIH1 in cardiac function and metabolism – HIF1 controls transcription of a series of metabolic genes. Little is known about the role of FIH1 in the heart, and we have found that disabling FIH1 function is consistent with a hypoxic phenotype, with abnormal calcium handling and upregulated carbohydrate metabolism. In light of this data, the PhD project will first investigate how FIH1 function controls metabolism, and how FIH1 interacts with HIF stabilisation and transcription are affected by varying FIH function, by both manipulation in vivo and via siRNA cell culture techniques. Of particular importance will be determining the partitioning of carbohydrate metabolism with FIH1 disruption, simultaneously measuring glycolytic flux and glucose oxidation – these experiments will be performed in intact, beating hearts. Finally, at the mitochondrial level, the influence of FIH1 will be examined, using electron microscopy techniques – FIH1-/- mice have been reported as hypermetabolic. The project offers the opportunity to experience a wide variety of laboratory techniques, which are of relevance to both cardiovascular and hypoxic research.

The University of Nottingham is one of the world’s most respected research-intensive universities, ranked 8th in the UK for research power (REF 2014). Students studying in the School of Life Sciences will have the opportunity to thrive in a vibrant, multidisciplinary environment, with expert supervision from leaders in their field, state-of-the-art facilities and strong links with industry. Students are closely monitored in terms of their personal and professional progression throughout their study period and are assigned academic mentors in addition to their supervisory team. The School provides structured training as a fundamental part of postgraduate personal development and our training programme enables students to develop skills across the four domains of the Vitae Researcher Development Framework (RDF). During their studies, students will also have the opportunity to attend and present at conferences around the world. The School puts strong emphasis on the promotion of postgraduate research with a 2-day annual PhD research symposium attended by all students, plus academic staff and invited speakers.