Significance of cytoskeletal filaments coordination in immunity and cell migration

PROJECT OVERVIEW

The cytoskeletal organisation is fundamental for all cellular events, which defines the shape of the cells, the transport of molecules in different cellular domains, and controls the dynamics of cellular function. It is organised according to the cellular polarity and controls the position of the cell surface receptors, adhesion molecules, and all associated molecules within the cells. When cells migrate, dynamic re-organisation of filamentous actin and microtubules are essential as all adhesion molecules and proteolytic enzymes need to be positioned at the right place at the right time, according to the cell shape. When T-cells communicate with antigen-presenting cells by forming immune synapses, all molecules need to be organised by targeted transport of molecules to the synapse along microtubules. All these events require coordination of actin and microtubule filaments. However, the mechanism of coordination of these cytoskeletal filaments is not understood. Recently we have identified a molecule that is necessary for this coordination. Cells lacking this molecule are unable to coordinate two cytoskeletal filaments; 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 examined in various cell types, including T-cells, myeloid cells and cancer cells, and investigate the roles of this molecule in T-cell functions, myeloid cell function and cancer invasion. This project provides a great opportunity to learn various molecular cell biological techniques, including genome editing, gene silencing and cutting-edge live cell imaging techniques. 

KEYWORDS 

Cytoskeleton, T-cells, Immune synapses, Cancer invasion 

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. 

KEY PUBLICATIONS 

1. V. Gifford, A. Woskowicz, N. Ito, S. Balint, B.C. Lagerholm, M.L. Dustin, Y. Itoh, Coordination of two kinesin superfamily motor proteins, KIF3A and KIF13A, is essential for pericellular matrix degradation by membrane-type 1 matrix metalloproteinase (MT1-MMP) in cancer cells, Matrix Biol 107 (2022) 1-23.
2. C. Cassioli, A. Onnis, F. Finetti, N. Capitani, J. Brunetti, E.B. Compeer, V. Niederlova, O. Stepanek, M.L. Dustin, C.T. Baldari, The Bardet-Biedl syndrome complex component BBS1 controls T cell polarity during immune synapse assembly, J Cell Sci 134(16) (2021).

KEY THEMES 

Tissue remodelling and regeneration
Immunity and microbiome