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NCKIR5: Coordination of microtubules and fibrillar actin re-organisation: roles in the function of adherent cells and immune cells


   Kennedy Institute of Rheumatology

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  Dr Yoshi Itoh, Prof M Dustin  No more applications being accepted  Funded PhD Project (Students Worldwide)

Oxford United Kingdom Immunology Medical Physics Microbiology

About the Project

The human body is made up of around 30 trillion cells, maintaining our life. Depending on the cell types, they have a size and a shape that directly link to their functionality. A cellular cytoskeleton, fibrillar actin, determines cell shape. The plasma membrane is backed up by actin, and the rearrangement of the actin cytoskeleton determines membrane dynamics. Thus, the cell functions are linked to actin dynamics. When cells change their membrane structures, molecular distribution within the cells or cell surface needs to be changed accordingly. All the molecules are distributed to a specific area of cells by trafficking along the microtubule cytoskeleton. Thus, when new membrane structures are generated by the re-organisation of the actin, microtubules also need to be re-organised to reach the new membrane structures. Therefore, coordination of actin and microtubule is crucial to localise proteins in a Spatio-temporal manner, maintaining proper cell function. However, the mechanism that allows the coordination of these two major cytoskeletons is not understood well to date. Recently we have identified a molecule that is necessary for this coordination. Cells lacking this molecule are unable to coordinate two cytoskeletons. Thus, they have a defect in delivering specific molecules to the right place at the right time. In this DPhil project, we will investigate the mechanism of this molecule to coordinate the two cytoskeletons. The role of this molecule will be further examined in various cell types, namely fibroblasts, epithelial cells, cancer cells, macrophages, and T-cell. We investigate the roles of this molecule in the cellular functions of these different cell types, including ECM degradation by fibroblasts, epithelial polarity, cancer cell invasion, macrophage phagocytosis, and formation of the T-cell immune synapse. This project provides an excellent opportunity to learn various molecular cell biological techniques, including gene editing, DNA construction and transfection, and cutting-edge live-cell imaging techniques.  

TRAINING OPPORTUNITIES:

The Kennedy Institute is a world-renowned research centre and is housed in a state-of-the-art research facility. Full training will be provided in a range of cell and molecular biology techniques. A core curriculum of 20 lectures will be taken in the first term of year 1 to provide a solid foundation in musculoskeletal sciences, immunology and data analysis. Students will attend weekly departmental meetings and will be expected to attend seminars within the department and those relevant in the wider University. Subject-specific training will be received through our group's weekly supervision meetings. Students will also attend external scientific conferences where they will be expected to present the research findings. Achieving this project will provide a significant information in fundamental cell biology, which contribute to understanding of cell function under pathophysiological conditions.


References

KEY PUBLICATIONS (5 maximum):
1. Gifford et al. (2021) Coordination of KIF3A and KIF13A regulates leading edge localization of MT1-MMP in cancer cells. BioRxiv. DOI. 10.1101/2021.05.24.445438
2. Weaver et al (2014) Basal localization of MT1-MMP is essential for epithelial cell morphogenesis in 3D collagen matrix. J Cell Sci. 127, 1203-13.
3. Demetriou et al (2020) A dynamic CD2-rich compartment at the outer edge of the immunological synapse boosts and integrates signals. Nat Immunol. 21, 1232-43
KEYWORDS: Micotubule, fibrillar actin, vesicle transport, Molecular Cell biology, microscopy
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