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Harnessing the crosstalk between extracellular matrix stiffness and tissue redox chemistry to modulate the fate of macrophages


   School of Life Sciences


About the Project

We are seeking a highly motivated candidate with strong academic background in immunology, chemistry, biology or related area for a multidisciplinary PhD project focused on development of biomaterials with immune modulatory properties with potential applications in immune therapy and vaccination.

Background and aims:

The immune microenvironment is a complex system and plays a critical role in biological processes of some of the most pressing healthcare challenges such as chronic inflammation, wound healing, cancer, and implant integration. Macrophages are a heterogeneous group of immune cells that play important roles in resolution of injury, infection and tumor growth. Like other types of immune cells, macrophages respond to different environmental cues including extracellular matrix (ECM) stiffness, redox state and cytokines and are thereby polarized into specialized functional subsets. The possibility to control macrophage polarization toward either pro-inflammatory (M1) or anti-inflammatory (M2) phenotype using matrix stiffness has been demonstrated however molecular mechanisms that drive such phenotypical changes have remained elusive [1]. Hypoxia (oxygen shortage) is another important tissue environmental factor, its impact on macrophage polarization and subsequent modification of the inflammatory microenvironment have not been fully established. Hypoxia can promote macrophages accumulation, polarization and modify the inflammatory microenvironment in most solid tumours, which are generally hypoxic, leading to poor prognosis. Modification of such microenvironment by molecular oxygen supply can switch macrophage phenotype between the tumour-associated M2 and the tumour-killing M1 phenotypes.

The proposed project aims to design a novel molecular hydrogel platform based on novel molecular materials [3-8] to create synthetic extracellular matrix with tunable stiffness and oxygen self-generation ability to modulate macrophage polarization. This system offers fundamental advantages over state-of-the-art approaches that either do not resemble the structural architecture of the native ECM, use cytokines/growth factors or rely on the non-tunable poorly defined matrixes such as Matrigel.

By tuning the mechanical properties of the hydrogels and the concentration of self-generated molecular oxygen, we aim to investigate the crosstalk between the hydrogel mechanics and molecular oxygen level on macrophage polarization and their respective molecular pathways. This information will aid the design of novel immune-instructive materials with desired immune regulatory properties that could be used for a range of applications including promoting pathogen clearance and  treating chronic inflammatory diseases such as cardiovascular disease, chronic wound and arthritis amongst others.

Training:

The project provides excellent training opportunities in cellular immunology techniques (e.g. immune cells isolation, macrophage differentiation and characterisation, co-cultures), ELISA, PCR, flow cytometry, confocal microscopy as well as a diverse range of synthetic chemistry, molecular characterisations, molecular self-assembly, materials characterizations, and a host of relevant analytical methods.


Funding Notes

Applicants should have a minimum 2.1 BSc in biology, chemistry, immunology or related discipline. Previous laboratory-based experience in a relevant area will be advantageous. Overseas applicants should fulfil the University of Nottingham English Language Requirements.
This project is only available to self-funded students.

References

1-Rostam, Ghaemmaghami et al. Immune-instructive polymers control macrophage phenotype and modulate the foreign body response in vivo. Matter 2020, 2, 1564-1581.
2-Kämmerling, Ghaemmaghami et al. Immune-instructive materials as new tools for immunotherapy. Curr Opin Biotechnol. 2022, 74,194-203.
3-Okesola et al. Supramolecular self-assembly to control structural and biological properties of multicomponent hydrogels. Chem. Mater. 2019, 31, 7883–7897.
4-Derkus, Okesola et al. Multicomponent hydrogels for the formation of vascularized bone-like constructs in vitro. Acta Biomater. 2020, 109, 82-94.
5-Okesola et al. Growth‐factor free multicomponent nanocomposite hydrogels that stimulate bone formation. Adv. Funct. Mater. 2020, 30, 190620.
6-Okesola et al. De Novo design of functional coassembling organic–inorganic hydrogels for hierarchical mineralization and neovascularization. ACS Nano 2021, 15, 11202–11217.
7-Isik et al. Mechanically robust hybrid hydrogels of photo-crosslinkable gelatin and laminin-mimetic peptide amphiphiles for neural induction. Biomater. Sci., 2021, 9, 8270-8284.
8-Isik, Okesola et al. Tuning the cell-adhesive properties of two-component hybrid hydrogels to modulate cancer cell behavior, metastasis and death pathways. Biomacromolecules, 2022, 23, 4254–4267

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