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  How to build and maintain a 3-dimensional polarised epithelial sheet


   School of Life Sciences

  Dr M Georgiou  Applications accepted all year round  Self-Funded PhD Students Only

About the Project

We are interested in how cells maintain normal cell shape within an epithelium. Correct epithelial cell shape is essential to maintain tissue integrity and when deregulated can cause diseases such as malignant cancers, diabetes, inflammation, and aging. This project offers a PhD student the exciting opportunity to work with three collaborating research groups, using state-of-the-art techniques, and using in vivo and in vitro systems, to better understand the molecular mechanisms underlying cell and tissue morphology.

Our recent work, using the living fruit fly as a model system, has begun to unravel the complex intracellular molecular machinery required for cells to take their characteristic shape and to correctly form and position sub-cellular structures, such as cell-cell junctions and dynamic protrusions. The PhD student will take this research further by working with three research groups in three Schools within the University of Nottingham: Dr Georgiou (Life Sciences) has developed tools that enable the labelling and manipulation of individual epithelial cells within the living fly. Dr Ashworth (Veterinary Medicine) has developed an advanced 3D in vitro culture system, allowing independent control over extra-cellular matrix (ECM) stiffness and composition. Dr Mendonca (Engineering) has developed ‘OptoRheo’, an optical instrument that enables non-destructive measurement of ECM stiffness at the microscale while also capturing corresponding live cellular dynamics using 3D light-sheet fluorescence microscopy. By combining the expertise of these groups, we aim to: (i) apply advanced imaging to our in vivo model using a customised light-sheet fluorescence microscope, developed by Dr Mendonca, to image cell morphology and dynamic protrusions in high temporal and spatial resolution in the living animal; (ii) transfer technology to in vitro models, using advanced biomaterials, to understand how properties of human stroma affect epithelial architecture and behaviour. We plan to use these complementary technologies to investigate the roles of ECM composition and stiffness in determining epithelial cell shape and tissue architecture. This will allow the link between epithelial sheet development and intracellular signalling to be explored in a system allowing precise tuning of ECM properties.

This project offers the student a fantastic opportunity to learn state-of-the-art techniques, including:

·      Sophisticated fly genetics

·      Live high-resolution imaging using confocal and light-sheet microscopy

·      Fly pupal mounting and dissections

·      Immunohistochemistry

·      Advanced 3D cell culture

·      Use of specialised imaging software

·      A wide variety of molecular biology techniques

·      Data analysis

·      Statistical analysis and numeracy skills

Biological Sciences (4) Physics (29)

References

• COUTINO, BRENDA CANALES, CORNHILL, ZOE E., COUTO, AFRICA, MACK, NATALIE A., RUSU, ALEXANDRA D., NAGARAJAN, USHA, FAN, YUEN NGAN, HADJICHARALAMBOUS, MARINA R., URIBE, MARCOS CASTELLANOS, BURROWS, AMY, LOURDUSAMY, ANBARASU, RAHMAN, RUMAN, MAY, SEAN T. and GEORGIOU, MARIOS, 2020. A Genetic Analysis of Tumor Progression in Drosophila Identifies the Cohesin Complex as a Suppressor of Individual and Collective Cell Invasion ISCIENCE. 23(6),
• COUTO A, MACK NA, FAVIA L and GEORGIOU M, 2017. An apicobasal gradient of Rac activity determines protrusion form and position. Nature communications. 8, 15385
• MACK NA and GEORGIOU M, 2014. The interdependence of the Rho GTPases and apicobasal cell polarity. Small GTPases. 5(2), 10
• BAUM, B. and GEORGIOU, M., 2011. Dynamics of adherens junctions in epithelial establishment, maintenance, and remodeling Journal of Cell Biology. 192(6), 907-917
• COHEN, M., GEORGIOU, M., STEVENSON, N.L., MIODOWNIK, M. and BAUM, B., 2010. Dynamic filopodia transmit intermittent Delta-Notch signaling to drive pattern refinement during lateral inhibition Developmental Cell. 19(1), 78-89
• GEORGIOU, M. and BAUM, B., 2010. Polarity proteins and Rho GTPases cooperate to spatially organise epithelial actin-based protrusions Journal of Cell Science. 123(7), 1089-1098
• GEORGIOU, M., MARINARI, E., BURDEN, J. and BAUM, B., 2008. Cdc42, Par6, and aPKC regulate Arp2/3-mediated endocytosis to control local adherens junction stability Current Biology. 18(21), 1631-1638
• ASHWORTH JC, THOMPSON JL, JAMES JR, SLATER CE, PIJUAN-GALITO S, LIS-SLIMAK K, HOLLEY RJ, MEADE KA, THOMPSON A, ARKILL KP, TASSIERI M, WRIGHT AJ, FARNIE G and MERRY, C. L. R., 2020. Peptide gels of fully-defined composition and mechanics for probing cell-cell and cell-matrix interactions in vitro Matrix Biology. 85-86, 15-33
• ASHWORTH JC, MORGAN RL, LIS-SLIMAK K, MEADE KA, JONES S, SPENCE K, SLATER CE, THOMPSON JL, GRABOWSKA AM, CLARKE RB, FARNIE, G and MERRY CLR, 2020. Preparation of a User-Defined Peptide Gel for Controlled 3D Culture Models of Cancer and Disease JOVE - Journal of Visualized Experiments.
• T. Mendonca, K. Lis-Slimak, A. B. Matheson, M. G. Smith, A. B. Anane-Adjei, J. C. Ashworth, R. Cavanagh, L. Paterson, P. A. Dalgarno, C. Alexander, M. Tassieri, C. L. R. Merry, A. J. Wright, 2023. OptoRheo: Simultaneous in situ micro-mechanical sensing and imaging of live 3D biological systems Communications Biology (in press).

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