The behaviour of cells is determined by how they interpret their genetic and epigenetic programming in the context of signals from their surroundings. These environmental cues are often chemical, but recent work has shown the importance of mechanical stimulation in driving responses to cell morphology, metabolism, motility, proliferation and commitment to lineage. More recently, variations in viscosity of the extracellular environment, as well as its rigidity, have been demonstrated to modulate cell signalling and alter phenotypic responses. However, very little is known about the mechanisms of viscosity sensing. Cells sense the mechanical properties of their environment through integrin adhesion receptors that bind and pull against components of the extracellular matrix (ECM). The modulated response to ECM stiffness, and its maintenance at the appropriate level, is essential for tissue health. The ECM is also central to many disease processes, and the aberrantly stiff, fibrotic environment of many cancers has been shown to contribute to uncontrolled cellular proliferation and metastatic processes. In pancreatic ductal adenocarcinoma (PDAC), for example, the ECM produced by pancreatic fibroblasts (PFs) is an order of magnitude stiffer than the healthy tissue.
Cells respond to physical stimuli, such as stiffness, through mechano-transduction pathways that convert mechanical to biochemical signals. Many of the proteins involved with these processes, such as components of the integrin adhesion complex (IAC) at the cell/ECM interface or the linker of nucleo- and cytoskeleton (LINC) complex at the nuclear membrane, have been identified and characterised. However, these complexes have generally been studied as discrete entities. We lack a holistic picture of how mechanical signals are carried from the ECM through to the nucleus, where distinct genetic programmes can be modulated.
Here we propose to use proximity biotinylation mass spectrometry (BioID-MS) to systematically identify the protein linkages that enable communication between cellular regulatory machinery and cellular environments with distinct viscoelastic properties. BioID-MS enables protein interactions to be identified by selectively tagging proteins proximal to a ‘bait’. By engineering a library of bait constructs for structural and signalling components of IACs, we will develop a quantitative, global picture of how PFs and PDAC cells respond to variable viscosity. We intend to identify conserved mechano-transduction pathways, as well as those that may be affected by disease and thus be future targets for intervention.
Eligibility
Applicants must have obtained or be about to obtain a First or Upper Second class UK honours degree, or the equivalent qualifications gained outside the UK, in an appropriate area of science, engineering or technology.
Before you Apply
Applicants must make direct contact with preferred supervisors before applying. It is your responsibility to make arrangements to meet with potential supervisors, prior to submitting a formal online application.
How To Apply
To be considered for this project you MUST submit a formal online application form - full details on eligibility how to apply can be found on the BBSRC DTP website https://www.bmh.manchester.ac.uk/study/research/bbsrc-dtp/
Your application form must be accompanied by a number of supporting documents by the advertised deadlines. Without all the required documents submitted at the time of application, your application will not be processed and we cannot accept responsibility for late or missed deadlines. Incomplete applications will not be considered. If you have any queries regarding making an application please contact our admissions team [Email Address Removed]
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