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MRC DiMeN Doctoral Training Partnership: Modelling the effects of inflammatory bowel disease on the immune response in synovial tissue


   MRC DiMeN Doctoral Training Partnership

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  Dr Priscila Melo, Prof Catharien Hilkens, Dr Ana Ferreira-Duarte  No more applications being accepted  Competition Funded PhD Project (Students Worldwide)

About the Project

Inflammatory bowel disease (IBD) is a chronic intestinal inflammation that causes epithelial injury. In the UK, around 620,000 people are thought to be affected by IBD, translating in NHS costs of about £1 billion per year. Clinically, up to 35% of patients with IBD display musculoskeletal disorders such as ankylosing spondylitis (AS) inferring that these two pathologies are connected. AS is centralized in synovial tissues and is caused by the overexpression of interleukin (IL)-23 and IL-17, both regulators of innate and adaptive immunity. IL-23 is involved in the differentiation of Th17 cells which produce IL-17. They are mainly found in mucosal tissues (e.g. bowel) however, they have been detected in synovial fluid of patients with both IBD and AS, inferring that dysregulation of the IL-17/IL-23 axis in the bowel leads to synovial inflammation through migration of pathogenic Th17 cells and/or associated inflammatory stimuli that, ultimately, leads to cartilage and bone destruction. The aim is to study this disease process by creating a novel 3D in vitro model of the human synovium using bioprinting and electrospinning, and subject it to Th17-related stimuli and/or cells that arise during IBD. A coculture 3D in vitro model will be created considering the synovium’s structure (intima and subintima), and base histological composition (macrophages and fibroblasts), to study changes in cell phenotype and secretion of soluble mediators, in both healthy and inflammatory states that are relevant to IBD. Then, the synovium model will be cocultured with a chondrocyte-based model as a read-out for cartilage damage.

This project combines skills in chemistry and materials sciences, design and manufacturing technology, tissue engineering and immunology to produce:

·      An electrospun membrane and 3D bioprinted constructs able to replicate the micro and nanostructure of the synovial membrane;

·      An in vitro model of the synovium through the design of 3D cocultures including synovial cells, seeded or embedded in the 3D structures;

·      Assess the response of the model to an external inflammatory stimulus provided by specific Th cells/cytokines seen in cases of IBD.

Therefore, the first stage of this project will be to study existing Extracellular Matrix‐Based materials (e.g. hyaluronic acid, collagen, ECM-like peptides, etc) as bioinks. The materials will be processed into 3D structures using bioprinting to achieve a spatial-temporal control the micro/nanoscale topographical and chemical features of the scaffold. The 3D structures will be tested for their physicochemical properties to ensure they match each layer of the synovial membrane. For this, a range of chemical (FTIR, XPS) and microstructural (SEM, TEM) analysis will be done, supported by rheological and mechanical testing (e.g. compression). The cell response and phenotype will be assessed to ensure it matches those of healthy conditions (e.g. viability and metabolic activity, gene expression).

This project is of high impact and has substantial potential to deliver long term benefits to patients affected by autoimmune diseases and chronic inflammatory diseases which impact people across the globe. New understanding of immune function is revealing exciting opportunities to help tackle these challenges by harnessing—or correcting—the specificity of immune function.

Dr. Priscila Melo (https://www.ncl.ac.uk/engineering/staff/profile/priscilamelo.html )

Professor Catharien Hilkens (https://www.ncl.ac.uk/medical-sciences/people/profile/catharienhilkens.html)

Dr Ana Marina Ferreira-Duarte (https://www.ncl.ac.uk/engineering/staff/profile/anaferreira-duarte.html)

Benefits of being in the DiMeN DTP:

This project is part of the Discovery Medicine North Doctoral Training Partnership (DiMeN DTP), a diverse community of PhD students across the North of England researching the major health problems facing the world today. Our partner institutions (Universities of Leeds, Liverpool, Newcastle, York and Sheffield) are internationally recognised as centres of research excellence and can offer you access to state-of the-art facilities to deliver high impact research.

We are very proud of our student-centred ethos and committed to supporting you throughout your PhD. As part of the DTP, we offer bespoke training in key skills sought after in early career researchers, as well as opportunities to broaden your career horizons in a range of non-academic sectors.

Being funded by the MRC means you can access additional funding for research placements, international training opportunities or internships in science policy, science communication and beyond. See how our current DiMeN students have benefited from this funding here: https://www.dimen.org.uk/blog

Further information on the programme and how to apply can be found on our website:

https://www.dimen.org.uk/how-to-apply


Funding Notes

Studentships are fully funded by the Medical Research Council (MRC) for 4yrs. Funding will cover tuition fees, stipend and project costs. We also aim to support the most outstanding applicants from outside the UK and are able to offer a limited number of full studentships to international applicants. Please read additional guidance here: https://www.dimen.org.uk/eligibility-criteria
Studentships commence: 1st October 2023
Good luck!

References

Melo, P.; Montalbano, G.; Fiorilli, S.; Vitale-Brovarone, C. 3D Printing in Alginic Acid Bath of In-Situ Crosslinked Collagen Composite Scaffolds. Materials 2021, 14, 6720. https://doi.org/10.3390/ma14216720
Melo, P.; Montalbano, G.; Boggio, E.; Gigliotti, C.L.; Dianzani, C.; Dianzani, U.; Vitale-Brovarone, C.; Fiorilli, S. Electrospun Collagen Scaffold Bio-Functionalized with Recombinant ICOS-Fc: An Advanced Approach to Promote Bone Remodelling. Polymers 2022, 14, 3780. https://doi.org/10.3390/polym14183780
Borciani, G.; Montalbano, G.; Melo, P.; Baldini, N.; Ciapetti, G.; Vitale-Brovarone, C. Assessment of Collagen-Based Nanostructured Biomimetic Systems with a Co-Culture of Human Bone-Derived Cells. Cells 2022, 11, 26. https://doi.org/10.3390/cells11010026
Leonie Schittenhelm, Jamie Robertson, Arthur G Pratt, Catharien M Hilkens, Vicky L Morrison, Dendritic cell integrin expression patterns regulate inflammation in the rheumatoid arthritis joint, Rheumatology, Volume 60, Issue 3, March 2021, Pages 1533–1542, https://doi.org/10.1093/rheumatology/keaa686
Spiering R, Jansen MAA, Wood MJ, Fath AA, Eltherington O, Anderson AE, Pratt AG, van Eden W, Isaacs JD, Broere F, Hilkens CMU. Targeting of tolerogenic dendritic cells to heat-shock proteins in inflammatory arthritis. J Transl Med. 2019 Nov 14;17(1):375. http://doi.org/10.1186/s12967-019-2128-4
Purvis HA, Anderson AE, Young DA, Isaacs JD, Hilkens CM. A negative feedback loop mediated by STAT3 limits human Th17 responses. J Immunol. 2014 Aug 1;193(3):1142-50. http://doi.org/10.4049/jimmunol.1302467
Montalbano, G., Toumpaniari, S., Popov, A., Duan, P., Chen, J., Dalgarno, K., Scott, W. E., 3rd, & Ferreira, A. M. (2018). Synthesis of bioinspired collagen/alginate/fibrin based hydrogels for soft tissue engineering. Materials science & engineering. C, Materials for biological applications, 91, 236–246. https://doi.org/10.1016/j.msec.2018.04.101
Ngadimin, K. D., Stokes, A., Gentile, P., Ferreira, A.M. Biomimetic hydrogels designed for cartilage tissue engineering. Biomater. Sci., 2021,9, 4246-4259. https://doi.org/10.1039/D0BM01852J
Kotlarz, M., Ferreira, A.M., Gentile, P. et al. Droplet-based bioprinting enables the fabrication of cell–hydrogel–microfibre composite tissue precursors. Bio-des. Manuf. 5, 512–528 (2022). https://doi.org/10.1007/s42242-022-00192-5
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