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Molecular nano-immunology and optical microscopy: the application and development of ultra-sensitive, live-cell fluorescence microscopy techniques with a spatial resolution down to the molecular level


Project Description

The Nano-Immunology group is based in the Human Immunology Unit at the MRC WIMM. The Group is headed by Prof Christian Eggeling, an expert in fluorescence microscopy and especially in the development and application of super-resolution fluorescence (STED) microscopy with a long-standing record in this field. The main research interests of the laboratory are focused on the application and development of ultra-sensitive, live-cell fluorescence microscopy techniques with a spatial resolution down to the molecular level (super-resolution microscopy or nanoscopy), superior to conventional optical microscopes. These super-resolution microscopes will be used to unravel nanoscopic changes at the molecular level in living cells following cellular immune responses. Projects aim at visualizing previously un-detectable molecular interactions (such as protein-protein and protein-lipid interactions), which will shed new light on different molecular pathways triggered at the cell surface and intracellularly, for example during antigen presentation by dendritic cells and T-cell activation. For further details see http://www.nano-immunology.org

The Group further has close links to the Wolfson Imaging Centre, which is an open-user image facility that was opened in May 2013. It currently hosts several state-of-the-art fluorescence microscopes, including a multi-photon upright, three inverted confocal (one with Airyscan detector), one fast wide-field deconvolution, one spinning disc, a unique (single-molecule and FLIM) super-resolution STED microscope, and a TIRF- and wide-field-based single-molecule and super-resolution PALM/dSTORM microscope. For more information, please visit http://www.imm.ox.ac.uk/imaging-and-microscopy.

The organization of immune-cell surfaces is presently a focus of intense interest for molecular immunologists, especially how proteins such as the T-cell receptor or antigen-presenting molecules change their organization and diffusion and interaction dynamics during activation and how other molecules and structures such as lipids or the actin cytoskeleton are involved. Revealing further details on this will help refining the search for effective antibodies against many diseases such as cancer and auto-immunity. Unfortunately, many details of protein/lipid organizations and interaction dynamics cannot accurately be determined in the living cell because of the limited spatial resolution of far-field optical fluorescence microscopy. While this imaging technique is currently probably the most valuable tool for directly investigating the living cell with minimal invasion, similar objects closer together than approximately 200 nm cannot be distinguished and details of molecular organization and dynamics on (macro)molecular scales cannot be recovered directly. A remedy to this is recently developed super-resolution optical microscopy or nanoscopy: approaches such as STED (stimulated emission depletion microscopy) have now evolved into superior tools for investigating cellular dynamics at the nanoscale. Specifically the combination of STED with fluorescence correlation spectroscopy (STED-FCS) has recently allowed unique insights into molecular plasma membrane dynamics and organization such as the potential formation of nanodomains (or lipid “rafts”).

We propose to characterize the organization and interaction dynamics of several proteins at the T-cell antigen-presenting surface such as T-cell receptor, Lck, CD45, CD1d, MHC 1 and 2 or MR1, both in relation to different lipids, and in comparison to other components of the signalling machinery of the immune cells, using advanced microscopy approaches such as STED(-FCS) microscopy. We expect these novel experiments to highlight, in thus far unprecedented detail, the organization of key signalling proteins at the immune cell surface, and to create a critical framework for understanding their triggering.

This project will be based in the MRC Human Immunology Unit at the Weatherall Institute of Molecular Medicine, with access to state-of-the-art facilities. The project provides an opportunity for training in a broad range of different techniques, such as cell culture, molecular biology, and microscopy, specifically including the unique STED-FCS super-resolution microscopy technique. The disclosure of novel details of immune cell activation is an important line of basic immunological research that may translate into new approaches of modulating the immune response during infection and may pave the way to new vaccine adjuvants. Close collaboration with many scientists will be required.

As well as the specific training detailed above, students will have access to high-quality training in scientific and generic skills, as well as access to a wide-range of seminars and training opportunities through the many research institutes and centres based in Oxford.

The Department has a successful mentoring scheme, open to graduate students, which provides an additional possible channel for personal and professional development outside the regular supervisory framework. We hold an Athena SWAN Silver Award in recognition of our efforts to build a happy and rewarding environment where all staff and students are supported to achieve their full potential.

Funding Notes

Funding for this project is available through the RDM Scholars Programme or the WIMM Prize Studentship. Both programmes offer funding to outstanding candidates from any country. Successful candidates will have all tuition and college fees paid and will receive a stipend of £18,000 per annum.

Applications must be received, including all relevant supporting materials, by Friday 11th January 2019 at 12 noon (midday).

Please visit our website for more information on how to apply.

References

Santos, A. M. et al. Capturing resting T cells: the perils of PLL. Nat Immunol 19, 203-205 (2018).

Fritzsche, M. et al. Cytoskeletal actin dynamics shape a ramifying actin network underpinning immunological synapse formation. Sci Adv 3 (2017).

Colin-York, H., Eggeling, C. & Fritzsche, M. Dissection of mechanical force in living cells by super-resolved traction force microscopy. Nat Protoc 12, 783-796 (2017).

Gutowska-Owsiak, D. et al. Orchestrated control of filaggrin-actin scaffolds underpins cornification. Cell Death & Disease 9, 412 (2018).

Sezgin, E., Levental, I., Mayor, S. & Eggeling, C. The mystery of membrane organization: composition, regulation and roles of lipid rafts. Nat Rev Mol Cell Biol 18, 361-374 (2017).

Chojnacki, J. et al. Envelope glycoprotein mobility on HIV-1 particles depends on the virus maturation state. Nat Commun 8, 545 (2017).

How good is research at University of Oxford in Clinical Medicine?

FTE Category A staff submitted: 238.51

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