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Developing a three-dimensional research model of neutrophil-mediated tissue destruction during inflammation


Project Description

Background:
The proposed research has the goal to develop a novel 3D model to measure and visualise tissue destruction mediated by migrating neutrophils in vitro.
In inflammation, leukocytes, predominantly neutrophils, migrate into the
inflamed/infected tissues. Whilst neutrophil defence strategies are aimed at protecting the host, they also cause unintentional collateral damage to the tissues. In chronic inflammation, this degradation leads to progressive and irreversible tissue destruction. Chronic inflammatory diseases are highly prevalent worldwide. Some examples are rheumatoid arthritis (RA), inflammatory bowel disease (IBD), chronic obstructive pulmonary disease and periodontitis. The latter involves progressive inflammatory destruction of the tooth-supporting tissues, eventually leading to tooth loss.

Our previous research has shown that neutrophils from periodontitis patients release tissue-damaging molecules in excess. These neutrophils also showed impaired migration capabilities, presumably prolonging their tissue transit time. The multiple abnormal neutrophil functionalities may lead to more pronounced tissue degradation in chronic inflammation, however, this remains to be demonstrated. The current evidence for tissue breakdown by neutrophils is derived from models that do not mimic real tissues adequately and do not enable the analysis of tissue damage.

The proposed model will be based on human gingival tissue explants and will allow to observe neutrophil behaviour during tissue transit microscopically and to quantify tissue breakdown products. It will provide a new system for studying tissue damage under various conditions of challenge and antagonists, including pro-resolving mediators. Importantly, this model could be used as a test kit for screening drugs targeting neutrophils in the academic and industry research environments.

The Periodontal Research Group at the Birmingham Dental Hospital (UK), has one open PhD position that offers the exiting possibility to develop a 3D model for neutrophil migration and chemotaxis. The PhD project would cover techniques such as isolation of neutrophils from human blood, preparing 3D matrices for neutrophil migration, neutrophil functional assays (e.g. reactive oxygen species release, phagocytosis) and microscopy methods. Strong collaborations with research partners providing expertise in neutrophil migration assays are in place and our laboratory has state-of-the-art equipment available, along with established protocols for cell functional assays. The outcomes of this study will not only be of interest to the periodontal research community, but are also likely to attract interest from other medical fields concerned with chronic destructive inflammation.

Objectives:
There are three main aims within this PhD project:

Firstly, learning existing neutrophil functional assays developed by our group as well as isolation methods.
This will include neutrophil isolation, stimulation with bacteria or bioactive substances and assay of reactive oxygen species, chemotaxis, phagocytosis, neutrophil extracellular trap release and cytokine production.

Secondly, developing 3D matrices for neutrophil migration assays.
This part of the PhD is the central goal of this project and will include working with gels, extracellular matrix components, gum tissue explants and isolated live neutrophils.

Thirdly, investigating the defence functions of neutrophils during and after migration through the 3D matrix or tissue section.
The aim is to show and visualise for the first time if and how neutrophils cause tissue destruction within their environment during migration.

Methods/techniques:
Isolation of neutrophils, neutrophil functional assays (reactive oxygen species and cytokine release assays, phagocytosis assays), design and fabrication of matrix gels of different compositions for cell migration, histology, live cell imaging and fluorescence microscopy, video microscopy, chemiluminescence, FACS and ELISA.

We will consider applications from prospective students with:
- a good biomedical, biology or similar degree (minimum of a 2:1)
- a source of funding to cover tuition fees and bench fees.

For more information regarding the project, please contact Dr J. Hirschfeld ().

For more information about the programme, eligibility, fees, application process please see https://www.birmingham.ac.uk/postgraduate/courses/research/dent/dentistry-phd.aspx or contact

Funding Notes


References

1. White PC, Hirschfeld J, Milward MR, Cooper PR, Wright HJ, Matthews JB,
Chapple ILC. Cigarette smoke modifies neutrophil chemotaxis, NET
formation and inflammatory response-related gene expression. J
Periodontal Res. 2018; 53(4):525-535
2. Hirschfeld J, White PC, Milward MR, Cooper PR, Chapple ILC. Modulation
of Neutrophil Extracellular Trap and Reactive Oxygen Species Release by
3. Periodontal Bacteria. Infect Immun. 2017 Nov 17; 85(12): e00297-17. Hirschfeld J, Roberts HM, Chapple IL, Parcina M, Jepsen S, Johansson A,Claesson R. Effects of Aggregatibacter actinomycetemcomitans leukotoxin on neutrophil migration and extracellular trap formation. J Oral Microbiol. 2016; 8:33070.
4. Ling MR, Chapple IL, Matthews JB. Peripheral blood neutrophil cytokine hyper-reactivity in chronic periodontitis. Innate Immun. 2015;21(7):714-25.
5. Roberts HM, Ling MR, Insall R, et al. Impaired neutrophil directional chemotactic accuracy in chronic periodontitis patients. J Clin Periodontol. 2015; 42(1):1-11.
6. Hirschfeld J, Dommisch H, Skora P, et al. Neutrophil extracellular trap formation in supragingival biofilms. IJMM 2015;305(4-5):453-63.
7. Hirschfeld J. Dynamic interactions of neutrophils and biofilms. J Oral Microbiol. 2014; 6:26102.
8. Matthews JB, Wright HJ, Roberts A, Cooper PR, Chapple ILC. Hyperactivity and reactivity of peripheral blood neutrophils in chronic periodontitis. Clin Exper Immunol. 2007; 147(2): 255-264.

How good is research at University of Birmingham in Allied Health Professions, Dentistry, Nursing and Pharmacy?

FTE Category A staff submitted: 15.90

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