How does the iron-mitochondria crosstalk influence the NRF2-cellular homeostatic mechanism in the human immune- and inflammatory response?
Supervisors:
Gwo-tzer Ho, School Infection and Immunity, University of Glasgow
James Brewer, School for Infection and Immunity, University of Glasgow
Caroline Dewar, Biomedical and Life Sciences, Lancaster University
Summary:
This PhD will investigate how ubiquitous iron influences mitochondria function and associated NRF2-mediated transcriptional responses in different tissues and cells. Mitochondria are intracellular organelles present in most eukaryotic cells, primarily to provide energy. The mitochondria, however, also play major roles in immunity, inflammation and cell death.
In health and disease settings, there are major shifts in iron that can affect mitochondrial function with different outcomes ranging to cell death (via ferroptosis) and inflammation. To maintain homeostasis, NRF2 is activated and induce different transcriptional programs with >200 genes involved. We postulate that these responses are unique in different tissue states, either driving inflammation or modifying the protective immune responses during infection. To address this, we will exploit spatial- and single-cell approaches to delineate NRF2-mediated transcriptional programs in relation to mitochondrial function. We will test how iron and mitochondrial function, in response to external inflammatory and immune-stimuli, determines the immune crosstalk, experimentally in vitro.
During this PhD, the successful candidate will receive training in complex human and mouse transcriptomic datasets, immunological experimental approaches and gain experience in studying mitochondrial biology. There will be exposure to human infective and immune disease such as malaria and IBD – major global diseases.
In summary, this PhD will investigate this important pathway in the human context with the opportunity to discover new underpinnings of tissue biology with a very experienced team of immunologist, mitochondrial and translational researchers in UK.