SWBio DTP (BBSRC funded): Understanding transcriptional control of autophagy during epithelial homeostasis and microenvironmental stress.
We are pleased to announce the opportunity to apply for this project as part of the South West Biosciences Doctoral Training Partnership (SWBio DTP) funded by the Biotechnology and Biological Sciences Research Council (BBSRC). This opportunity is fully funded and full time.
The SWBio DTP offers projects in world-class bioscience. This studentship encompasses the area of bioscience for an integrated understanding of health.
The closing date for applications is midnight on Monday 7 December 2020.
This project is a standard DTP studentship with an associate partner where you will be required to spend time with each of the partners, which are University of the West of England (UWE Bristol) and the University of Bristol.
A fundamental challenge in biology is understanding how cells respond and adapt to environmental changes to maintain tissue homeostasis. Intestinal epithelial cells lining the gut are continually subjected to microenvironmental stresses. They use adaptive signalling to tolerate these stresses, and failures in these mechanisms can undermine tissue fitness and gut barrier function, contributing to age-related diseases including inflammation and cancer.
One physiological stress encountered by intestinal epithelial cells is reduced oxygen availability (hypoxia). This occurs under homeostatic conditions due to fluctuating metabolic demands and counter-current blood flow. Cells sense and respond to oxygen deprivation by switching on hypoxia-inducible factors (HIFs), transcription factors that increase the expression of genes involved in adaptive processes, such as autophagy, an essential stress response pathway. Autophagy transcriptional control in the gut is also influenced by Wnt/beta-catenin signalling, and by YAP, a Hippo pathway effector that induces a transcriptional programme favouring cell survival and tissue regeneration.
We have recently discovered an exciting new regulatory axis involving the induction of an uncharacterised G-protein coupled receptor (GPCR) that signals via YAP to enable hypoxic cell survival. Newly acquired data from genetic loss-of-function studies indicate that this receptor may suppress Wnt/beta-catenin signalling to trigger the autophagy response during hypoxia. We suspect that failure to activate this signalling axis may uncouple the Wnt/beta-catenin and autophagy pathways, compromising the adaptive cellular response and resulting in tissue damage.
This project will determine the role of this new GPCR during normal intestinal homeostasis and upon exposure to physiological hypoxia, focusing on its interactions with the Wnt/beta-catenin and Hippo/YAP pathways. In a multidisciplinary research programme using ex-vivo 3D organoid culture models of the intestinal epithelium, you will investigate how this GPCR shapes normal epithelial homeostasis and the response to low oxygen stress. Loss of function organoid models will be generated using CRISPR-Cas9 for stem cell and differentiation assays, for autophagic flux and metabolic analysis. This will be combined with integrative ‘omics’ characterisation of the GPCR-regulated transcriptome/proteome using RNA-seq and quantitative proteomic approaches, respectively.
Training will be provided in advanced cell biology and ‘omics’ techniques, including stem cell culture, widefield and confocal microscopy, bioinformatics, and CRISPR-mediated genome editing, in modern laboratories supported by cutting edge microscopy and proteomics facilities.
- Lead supervisors: Dr Jon Lane (University of Bristol), Dr Alexander Greenhough (UWE Bristol)
- Prof Ann Williams (University of Bristol)
- Dr Tim Craig (UWE Bristol)
- Prof Stefan Roberts (University of Bristol)
- Dr Dann Turner (UWE Bristol)
- Dr Kate Heesom (University of Bristol)
- Prof Paloma Ordonez Moran (University of Nottingham)
- University of Bristol and UWE Bristol