About the Project
Understanding why certain individuals respond to treatments and others do not represents a significant knowledge gap in all of applied medicine. Better means of delineating the patients who will respond best to which therapeutic options would invoke a step-change in the delivery of health care and lead to treatments tailored to each individual patient. Additionally, understanding why certain patients don’t respond well to treatments would provide equally important insight.
Our work focuses on inflammatory disorders at the oral barrier, specifically the development of Periodontitis, the most common chronic inflammatory disease world-wide, affecting almost 50% of the UK population. During routine medical checks on patients suffering from other chronic inflammatory disorders, such as COPD, rheumatoid arthritis, and diabetes, presence or absence of oral disease is rarely considered. This is a significant oversight as periodontitis has been shown to lead to an increased risk of developing, as well as exacerbating, these and other severe inflammatory conditions. Yet how localised inflammation at the oral barrier can potentiate these other diseases at sites far away from the mouth is unknown. This project will begin to understand how periodontal disease impacts systemic immune functioning, specifically elucidating how oral inflammatory mediates inflammatory consequences in the lung and contributes to inflammatory lung pathology.
Our innovative study will provide detailed, mechanistic understanding of how oral inflammation modulates lung immune responses. Data generated will improve our current understanding of the immunological dialog between the oral and lung mucosal barriers. Utilizing murine models of disease alongside human samples, we will employ multicolour flow-cytometry, genome-wide transcriptional profiling and histological strategies to define alterations to immunologic parameters. This will be coupled with detailed examination of oral and lung microbial communities and the impact of these altered communities on immune functionality. Combined, this approach will allow us to elucidate both the cellular and molecular mediators promoting lung inflammatory consequences during oral inflammation.
Importantly, elucidating the systemic inflammatory consequences of periodontitis will allow for a better understanding of disease pathology in chronic lung inflammatory disease, such as COPD, providing essential information for the development of therapeutics for these life-limiting diseases. In particular realization of the aims laid out in this application will importantly identify novel mechanisms of patient stratification. Utilization of oral health parameters, alongside the systemic inflammatory outcomes of periodontitis, will provide new, and straight-forward, mechanisms to improve patient stratification and implementation of personalized medicine in the treatment of inflammatory lung diseases.
http://www.mccir.ls.manchester.ac.uk/research/tissuespecificimmunecellnetworks/
http://www.mccir.ls.manchester.ac.uk/research/inflammatorycellfunction/
http://www.mccir.ls.manchester.ac.uk/research/lungimmunity/
This is a potential studentship to be funded via the MRC Doctoral Training Programme. Projects under this scheme are competitively funded; i.e. there are more projects advertised than available.
Funding Notes
Please make direct contact with the Principal Supervisor to arrange to discuss the project and submit an online application form as soon as possible. There is no set closing date; projects will be removed as soon as they are filled.
Applications are invited from UK/EU nationals. Candidates from outside of the UK must have resided in the UK for 3 years prior to commencing the PhD in order to be eligible to apply. Applicants must have obtained, or be about to obtain, at least an upper second class honours degree (or equivalent) in a relevant subject.
References
1) On-going Mechanical Damage from Mastication Drives Homeostatic Th17 Cell Responses at the Oral Barrier. Dutzan N, Abusleme L, Bridgeman H, Greenwell-Wild T, Zangerle-Murray T, Fife ME, Bouladoux N, Linley H, Brenchley L, Wemyss K, Calderon G, Hong BY, Break TJ, Bowdish DM, Lionakis MS, Jones SA, Trinchieri G, Diaz PI, Belkaid Y, Konkel JE, Moutsopoulos NM. Immunity. 2017 Jan 17;46(1):133-147.
2) Characterization of the human immune cell network at the gingival barrier. Dutzan N, Konkel JE+, Greenwell-Wild T, Moutsopoulos NM. Mucosal Immunol. (2016) Sep;9(5):1163-72.
3) Isolation, Characterization and Functional Examination of the Gingival Immune Cell Network. Dutzan N, Abusleme L, Konkel JE*, Moutsopoulos NM. J Vis Exp. (2016) Feb 16;(108):53736.
4) Bone-Marrow-Resident NK Cells Prime Monocytes for Regulatory Function during Infection. Askenase MH, Han SJ, Byrd AL, Morais da Fonseca D, Bouladoux N, Wilhelm C, Konkel JE, Hand TW, Lacerda-Queiroz N, Su XZ, Trinchieri G, Grainger JR*, Belkaid Y. Immunity. (2015) Jun 16;42(6):1130-42.
5) Periodontitis: from microbial immune subversion to systemic inflammation. Hajishengallis G. Nat Rev Immunol. (2015) Jan;15(1):30-44.
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