Developing novel glycan-nanoparticle probes to elucidate dendritic cell immune modulation mechanisms

About the Project

Lectins are glycan binding proteins on immune cells that differentiate glycan patterns between normal and pathogens/disease cells to activate immune responses for protection. Evidence suggests that lectins, instead of specializing individually for pathogen or healthy cell glycan recognition, work cooperatively to complete tasks. Hence, a relatively small number of lectins can differentiate many pathogens or diseases/healthy cells to fine tune immune responses. However, the relationship between lectin combination and immune actions and how different lectin combinations modulate immune cell responses remains unclear. Moreover, it has been found that some pathogens (e.g., HIV) and cancer cells can exploit their glycan patterns to evade immune surveillance. Hence, revealing the relationship and underlying modulation mechanisms will not only advance our fundamental understanding of this important biological process but also guide the development of effective interventions against viral infection and cancer.

We have recently pioneered a powerful glycan-nanoparticle (NP) probe for successfully elucidating DC-SIGN- (a key DC surface immune lectin) glycan multivalent binding mechanisms. Here, we will extend our glycan-NP probe at the cellular level, exemplified using dendritic cell (DC), the most important pathogen presenting cell to dictate immune response. We will construct glycan-NPs with structures mimicking those of pathogens and/or healthy cells and use them to stimulate and measure DC immune responses. We will then pull down all glycan-NP bound lectins conveniently, via centrifugation facilitated by NP’s high density, and identify the lectins involved by mass spectroscopy. Combing the results will allow us to establish the correlation between lectin engagement and DC immune function regulation, using lectins’ native glycan instead of artificial antibody ligands. Moreover, the glycan-NP pull-down can also identify intracellular signalling proteins bound to the engaged lectins. Such proteins are directly involved in DC functioning. Together, these results will allow us to elucidate DC immune modulation mechanisms upon glycan-stimulation.

In this project, you will join a vibrant and highly stimulating research environment within the renowned Astbury Center for Structural Molecular Biology at the University of Leeds. You will receive training on organic ligand synthesis, glycan-NP construction and characterization, cell culture, and mass spectroscopy.

As a candidate, you will preferably have interests in exploring novel hypotheses and multidisciplinary techniques to reveal biological details. Ideally, you will have a strong background in synthetic chemistry or chemical biology. Knowledge of nanochemistry, protein biochemistry, protein mass spectroscopy, and/or cell culture will be advantageous. Motivation, creativity, excellent communication and team working skills are highly desirable.

Funding Notes

This is not a funded project, but you can apply for funding separately. Self-funding students are also welcome to apply.

Project supervisors

Dr Yuan Guo

Prof Dejian Zhou