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Mechanistic studies relating to vitamin D deficiency and sepsis severity


Project Description

Vitamin D deficiency as a therapeutic target in pneumonia, sepsis and ARDS: Although traditionally associated with calcium homeostasis, the last 20 years has witnessed a role for vitamin D as a modulator of the innate and adaptive immune system, preventing excessive expression of inflammatory cytokines and increasing antimicrobial responses (cathelicidin and -defensin), and the ‘oxidative burst’ potential of macrophages.3 Epidemiological studies have suggested a role for vitamin D status in the risk of developing both viral and bacterial infection.4,5 Our observational studies in over 500 patients have found that vitamin D deficiency (serum concentrations of 25-hydroxyvitamin D (25D3) less than 50nmol/L) is common in patients with severe sepsis and ARDS. Severe 25D3-deficiency is associated with an elevated systemic inflammatory response and an increased risk of developing ARDS in patients undergoing oesphagectomy. Furthermore, 25D3 levels are lower in those patients who die from sepsis within 30 days of admission to hospital, have bacteraemia, and levels correlate negatively with the severity of systemic acidosis.

We hypothesize that vitamin D regulates inflammatory responses to infection via dual specificity phosphatase 1 (DUSP1) and Tristetraprolin (TTP). Both TTP and DUSP1 are critical negative regulators of inflammatory responses to pathogens, and responses to experimental sepsis are exaggerated in mice lacking either protein. TTP is an mRNA destabilizing factor that targets several pro-inflammatory mRNAs, such as TNF, IL-1b and IL-6.14 Its anti-inflammatory function is inactivated by phosphorylations that are controlled by the MAPK p38 pathway. DUSP1 controls the activity of TTP indirectly, by regulating MAPK p38 signalling.15 Collaborator A Clark recently described a knock-in mouse strain in which the p38-dependent phosphorylation sites are mutated, and TTP is rendered constitutively active. These mice were resistant to LPS-induced endotoxic shock.Most importantly, both TTP and DUSP1 genes have been identified as direct targets of the Vitamin D receptor. Macrophages lacking DUSP1 were insensitive to inhibitory effects of vitamin D on MAPK p38 activity and expression of TNF and IL-6. Our working hypothesis is that vitamin D constrains responses of monocytes or macrophages to PAMPs 1) by increasing the expression of TTP and 2) by increasing the expression of DUSP1, thereby favouring the dephosphorylation and activation of TTP.

Person Specification
Applicants should have a strong background in molecular biology, and ideally a background in mouse work. They should have a commitment to research in respiratory / inflammation research and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in a relevant subject.

How to apply
Informal enquiries should be directed to Professor Thickett 0121 371 4841.

To apply, please send:
• A detailed CV, including your nationality and country of birth;
• Names and addresses of two referees;
• A covering letter highlighting your research experience/capabilities;
• Copies of your degree certificates with transcripts;
• Evidence of your proficiency in the English language, if applicable.

Funding Notes

Self-funded students only. This PhD would require funding for animal husbandry and consumables of £15,000 per year.

References

Background relevant publications:

Vitamin D Deficiency in Human and Murine Sepsis. Parekh D, Patel JM, Scott A, Lax S, Dancer RC, D'Souza V, Greenwood H, Fraser WD, Gao F, Sapey E, Perkins GD, Thickett DR. Crit Care Med. 2017 Feb;45(2):282-289.

Vitamin D deficiency contributes directly to the acute respiratory distress syndrome (ARDS). Dancer RC, Parekh D, Lax S, D'Souza V, Zheng S, Bassford CR, Park D, Bartis DG, Mahida R, Turner AM, Sapey E, Wei W, Naidu B, Stewart PM, Fraser WD, Christopher KB, Cooper MS, Gao F, Sansom DM, Martineau AR, Perkins GD, Thickett DR. Thorax. 2015 Jul;70(7):617-24.

Association between prehospital vitamin D status and incident acute respiratory failure in critically ill patients: a retrospective cohort study.Thickett DR, Moromizato T, Litonjua AA, Amrein K, Quraishi SA, Lee-Sarwar KA, Mogensen KM, Purtle SW, Gibbons FK, Camargo CA Jr, Giovannucci E, Christopher KB. BMJ Open Respir Res. 2015 Jun 13;2(1):e00007

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