Postgraduate research opportunities Mechanism of action and therapeutic potential of the anti-inflammatory parasitic worm product ES-62

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Key facts

  • Opens: Thursday 17 December 2020
  • Number of places: 1

Overview

Parasitic worm; immunomodulation; inflammation; anti-inflammatory drug development
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Eligibility

Second Class Honours Degree in Immunology, Microbiology, Parasitology or related discipline.

THE Awards 2019: UK University of the Year Winner
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Project Details

The hygiene hypothesis aims to explain the increased prevalence of diseases associated with aberrant inflammation (e.g., allergic and autoimmune conditions) in developed countries as being due to improved sanitation and hygiene in modernised societies. In other words, a lack of infections in childhood, as the immune system matures, prevents us from obtaining a system that has developed normally. Certainly, in unindustrialised countries, where often sanitation is reduced and medical treatment is less well established, there is evidence that childhood exposure to pathogens and infectious agents may protect against the development of such diseases. This concept has been particularly investigated with respect to helminth (worm) parasites and towards this we have shown in the laboratory that ES-62, a protein secreted by the filarial nematode Acanthocheilonema viteae, is able to prevent disease development and/or progression in mouse models of asthma, skin allergy, rheumatoid arthritis, systemic lupus erythematosus and the co-morbidities of obesity-accelerated ageing, e.g., gut pathology. We have extensively investigated the mechanism of action of ES-62 and found it to subvert immune system cell signalling pathways, e.g., it disrupts Toll-like receptor (TLR) signalling by promoting degradation of the TLR adaptor MyD88 and this resets the balance of cells like B lymphocytes from pathogenic effector to non-pathogenic regulatory forms. In addition, we have found ES-62’s active ingredient to be an unusual post-translational modification, phosphorylcholine (PC) attached to an N-type glycan, and we have thus produced a library of PC-based drug-like small molecule analogues (SMAs) that mirror the properties of the parent molecule. The overall aim of this project will thus be to further investigate the mechanism of action and therapeutic potential of ES-62/SMAs with respect to inflammatory diseases, which afflict humans, and for which new treatments are urgently required.

Techniques used: various immunological (e.g., flow cytometry; ELISA), molecular biological (e.g., RT-PCR) and in vivo biology procedures

Further information

Project suitable for:

 - Fully-funded students 

 - Self-funded students 

 

References 

The parasitic worm product ES-62 promotes health- and life-span in a high calorie diet-accelerated mouse model of ageing. Crowe J, Lumb FE, Doonan J, Broussard M, Tarafdar A, Pineda MA, Landabaso C, Mulvey L, Hoskisson PA, Babayan SA, Selman C, Harnett W, Harnett MM. PLoS Pathog. 2020 Mar 12;16(3):e1008391. doi: 10.1371/journal.ppat.1008391. eCollection 2020 Mar.


Synthetic small molecule analogues of the immunomodulatory Acanthocheilonema viteae product ES-62 promote metabolic homeostasis during obesity in a mouse model.

Lumb FE, Crowe J, Doonan J, Suckling CJ, Selman C, Harnett MM, Harnett W. Mol Biochem Parasitol. 2019 Dec;234:111232. doi: 10.1016/j.molbiopara.2019.111232. Epub 2019 Oct 18.

 

The parasitic worm product ES-62 normalises the gut microbiota bone marrow axis in inflammatory arthritis. Doonan J, Tarafdar A, Pineda MA, Lumb FE, Crowe J, Khan AM, Hoskisson PA, Harnett MM, Harnett W. Nat Commun. 2019 Apr 5;10(1):1554. doi: 10.1038/s41467-019-09361-0.

 

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Funding details

To be considered for this project applicants must be funded or be able to self fund the duration of their studies, covering tuition fees and a bench fee of £10.000 per annum

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Supervisors

Professor William Harnett

Strathclyde Institute of Pharmacy and Biomedical Sciences

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Contact us

Primary Supervisor: William Harnett

 Email: w.harnett@strath.ac.uk