Human tissues are complex architectures made up of a combination of cells spatially organised within a distinct extracellular matrix (ECM). Cells make and maintain the ECM, through which they receive biochemical, mechanical, and topological stimuli that are crucial to establishing and maintaining tissue function (1). This relationship is central to our understanding of a diverse range of biological processes, from development to ageing, and in diseases such as fibrosis (2) and cancer (3). We are particularly interested in the study of breast cancer, the second highest cause of mortality in women. After ageing, the highest risk predictor for breast cancer is high mammographic density (MD) - the opacity of breast tissue observed in a mammogram. Little is known about why high MD correlates with risk, although our work suggests that it is in part due to a fault in mechanical signalling. Mechanobiology explains how cells respond to stiffness, which can alter gene expression and promote cancerous changes in mammary epithelial cells, as well as the mechanically-induced behaviours of fibroblasts that drive tumour formation and fibrosis. This project aims to uncover how mechanical signals cause changes in cells by screening for proteins that are translocated into the nucleus in stiff environments. YAP is well known to mechano-biologists as a key mediator of mechano-sensitive cellular behaviours. In stiff environments, YAP is ‘switched on’ by translocation to the nucleus – a process thought to be regulated by mechanical opening of the nuclear pores and active transport mediated by proteins such as exportin-1 (XPO1). However, YAP alone cannot explain complex mechanically-mediated cellular programmes. We propose to adapt a strategy developed by Tseng et al. (4), using proximity labelling to tag and identify proteins that are translocated to the nuclei of epithelial and fibroblast cells cultured in stiff, three-dimensional culture models that mimic disease-prone tissue. Looking forward, the identification of key mechano-sensitive signalling pathways that drive ECM remodelling will inform the development and application of therapeutics to modulate the risk and progression of disease.
Entry Requirements
Applicants should hold (or be about to obtain) a First or Upper Second class (2:1) UK honours degree, or international equivalent, in a relevant subject.
Application Guidance
Candidates must contact the primary supervisor before applying to discuss their interest in the project and assess their suitability.
Apply directly via this link: https://tinyurl.com/zycedema or on the online application portal, select BBSRC DTP PhD as the programme of study. You may apply for up to two projects within this scheme. To do so, submit a single online application listing both project titles and the names of both main supervisors in the relevant sections.
Please ensure that your application includes all required supporting documents:
Curriculum Vitae (CV)
Supporting Statement
Academic Certificates and Transcripts
Incomplete or late applications will not be considered. Further details are available on our website: BBSRC North West Doctoral Programme in Bioscience | Biology, Medicine and Health | The University of Manchester
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