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How do macrophages regulate TNF release to maintain a healthy inflammatory response? (TROEBERGU19MED)


Project Description

Tight regulation of inflammation is critical for health, with conditions such as rheumatoid arthritis, Crohn’s disease and many others linked to dysregulated, chronic inflammation. Our research aims to understand the molecular mechanisms that control the inflammatory response in macrophages, so that we can develop novel therapies for such chronic inflammatory conditions.

We recently described a novel pathway that regulates resolution of inflammation by terminating release of the pleiotropic cytokine TNF from macrophages (Schubert et al, 2019, J Immunol). This pathway involves shedding of the endocytic receptor LRP1, which allows a build-up of the endogenous metalloproteinase inhibitor TIMP-3 on the cell surface, quenching release of TNF by the ‘sheddase’ ADAM17.

This PhD project will investigate how the LRP1 pathway is regulated in macrophages. The student will use cell culture, protein biochemistry and immunological analyses to address the following questions:
(i) Which enzyme(s) control shedding of LRP1 in macrophages?
(ii) Can use small molecule drugs to alter the rate of LRP1 shedding?
(iii) What molecules retain TIMP-3 on the macrophage cell surface?

The PhD project offers strong training and research experience in biological chemistry, analytical biochemistry, enzymology and cell biology. You will present your work at research seminars and scientific conferences, and learn important transferrable skills, such as project management, scientific writing and presentation. The project is well suited for a creative and ambitious student with a degree in Biochemistry, Biological Chemistry or a related discipline.

For more information on the supervisor for this project, please go here: https://people.uea.ac.uk/en/persons/l-troeberg/info?type=researchinterests
The type of programme: PhD
The start date of the project: Oct 2019
The mode of study: Full-time
Entry requirements: Acceptable first degree in biological sciences, biochemistry, immunology or equivalent and minimum 2:1

Funding Notes

This PhD studentship is funded by Norwich Medical School. Funding comprises Home/EU fees and a stipend of £15,009 and £1000 per annum to support research training. Overseas applicants may apply but are required to fund the difference between home/EU and overseas tuition fees (in 2019/20 the difference is £14,373 for Norwich Medical School but fees are subject to an annual increase).

References

1. Schubert K, Collins LE, Green P, Nagase H, Troeberg L (2019) LRP1 controls TNF release via the TIMP-3/ADAM17 axis in endotoxin-activated macrophages. In press, J. Immunol.
2. Collins LE, Troeberg L (2019) Heparan sulfate as a regulator of inflammation and immunity. J. Leukoc Biol. 105(1): 81-92.
3. Doherty CM, Visse R, Dinakarpandian D, Strickland DK, Nagase H, Troeberg L (2016) Engineered Tissue Inhibitor of Metalloproteinases-3 variants resistant to endocytosis have prolonged chondroprotective activity. J. Biol Chem. 291: 22160-72.

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