Chat online with top universities at our virtual study fair - Tuesday 7th July (12pm - 5pm BST)

University of East Anglia Featured PhD Programmes
Xi’an Jiaotong-Liverpool University Featured PhD Programmes
University of Reading Featured PhD Programmes

Establishing a rationale for FGF23 modulation as a therapy in the critically ill patient


Institute of Inflammation and Ageing

This project is no longer listed on FindAPhD.com and may not be available.

Click here to search FindAPhD.com for PhD studentship opportunities
Dr D Parekh , Prof D Thickett , Dr A Scott No more applications being accepted Funded PhD Project (UK Students Only)

About the Project

Research interests/description of main research theme:

Everyone suffers at least one critical illness during their life. In the UK, 160,000 critically ill patients are admitted annually to intensive care units (ICU). Mortality rates in hospital are ~20% and critical illness survivors have increased mortality, morbidity (physical, cognitive and psychological) and social care needs in the 5 years following discharge.

Most causes of critical illness involve infection with sepsis, immunosuppression or inflammation secondary to trauma or complications following major surgery. Sepsis is a particularly important cause of critical illness that is increasing in incidence with both bacterial and viral pneumonia as the commonest causes. When a patient becomes critically ill, this adversely affects both the adaptive and innate immune system with significant dysregulation of almost all inflammatory, coagulation, and metabolic pathways.

In health, fibroblast growth factor 23(FGF23) is an endocrine hormone mainly produced by osteocytes and osteoblastic cells, which is classically involved in the homeostasis of vitamin D and contributes to regulation of calcium and phosphate. FGF23 also has a wider direct role in the regulation of host innate immune and inflammatory responses. Multiple recent studies suggest that iron deficiency, Hypoxia Inducible Factor(HIF)-1α and systemic inflammation also upregulate FGF23 production. Although there is suggestion of increased mortality, acute kidney injury, myocardial function and infection in acute illness associated with raised FGF23, the role of FGF23 biology has not been extensively studied in patients with acute inflammation in sepsis/critical illness.

Hypothesis:

1) Acute inflammation drives FGF23 release that directly impairs innate immune responses in critical illness/sepsis leading to adverse clinical outcomes.

2) Dysregulated FGF23 leads to vitamin D catabolism in critical illness promoting an exaggerated deficiency, poor response to replacement therapy and counters the effects of vitamin D on inflammation and innate immune responses.

Research Objectives:

1) To characterize the effects of FGF23 upon macrophage and neutrophil function in critically ill patients enrolled in the VITDALIZE UK trial compared to age matched healthy controls. We will study FGF23 release, expression of FGFR/Klotho receptors as well as effects of FGF23 and FGF23 blockage upon cellular function (bacterial phagocytosis, efferocytosis, neutrophil apoptosis and chemotaxis).

2) To establish whether FGF23 release is a mechanistic driver of sepsis. We will determine in a mouse model of sterile inflammation and infection/sepsis whether FGF23 blockade reduces inflammation in VD sufficient and deficient mice.

3) To determine the dynamics of any relationship between FGF23, the vitamin D metabolome and critical illness. We will assess sequential changes in the relationship between FGF23 and the VD metabolome in patients from the VITDALIZE UK trial, and whether FGF23 levels determine the success of VD replacement

Our research group is based within the newly built Queen Elizabeth Hospital in a state of the art clinical research/laboratory facility. Working with University Hospitals Birmingham, we have unique access and capacity to recruit and study critically ill patients, with laboratories directly adjacent to the largest dedicated ICU in Europe. Using the skills of our multi-disciplinary team, including basic scientists, doctors, nurses, allied health care professionals and physiologists, we are working together to better understand underlying disease mechanisms.

The student will receive support from post docs and technicians within the group to help them achieve their goals- our group has a very collaborative ethos. The student will be encouraged to present data at national/international meetings. Students from our lab have been very successful winning prizes at national and international conferences, including; British thoracic society, Europe a thoracic society conference and American thoracic society scientific meeting.

Person Specification
Applicants should have a strong background in laboratory research, and ideally a background in macrophage biology, inflammation and murine studies. They should have a commitment to research in Inflammation biology and hold or realistically expect to obtain at least an Upper Second Class Honours Degree in Medical Sciences or Inflammation or Immunology.

How to apply

Informal enquiries should be directed to Dr Dhruv Parekh [Email Address Removed]

Applications should be directed to Dr Dhruv Parekh (email [Email Address Removed]).
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

This 4 year programme is funded by The Lorna & Yuti Chernajovsky Biomedical Research Foundation – the scholarship will cover PhD Stipend (as defined by UKRI), consumables and PhD fees.

References

Azoulay E, Vincent JL, Angus DC, et al. Recovery after critical illness: putting the puzzle together-a consensus of 29. Crit Care 2017;21:296.
Martin A, Quarles LD. Evidence for FGF23 involvement in a bone-kidney axis regulating bone mineralization and systemic phosphate and vitamin D homeostasis. Adv Exp Med Biol 2012;728:65-83.
Francis C, David V. Inflammation regulates fibroblast growth factor 23 production. Curr Opin Nephrol Hypertens 2016;25:325-32.
Babitt JL, Sitara D. Crosstalk between fibroblast growth factor 23, iron, erythropoietin, and inflammation in kidney disease. Curr Opin Nephrol Hypertens 2019;28:304-10.
Rossaint J, Oehmichen J, Van Aken H, et al. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest 2016;126:962-74.
Yang K, Peretz-Soroka H, Wu J, et al. Fibroblast growth factor 23 weakens chemotaxis of human blood neutrophils in microfluidic devices. Sci Rep 2017;7:3100.
Isakova T, Cai X, Lee J, et al. Longitudinal FGF23 Trajectories and Mortality in Patients with CKD. J Am Soc Nephrol 2018;29:579-90.
Schnedl C, Fahrleitner-Pammer A, Pietschmann P, Amrein K. FGF23 in Acute and Chronic Illness. Dis Markers 2015;2015:358086.
Leaf DE, Siew ED, Eisenga MF, et al. Fibroblast Growth Factor 23 Associates with Death in Critically Ill Patients. Clin J Am Soc Nephrol 2018;13:531-41.
Fuernau G, Pöss J, Denks D, et al. Fibroblast growth factor 23 in acute myocardial infarction complicated by cardiogenic shock: a biomarker substudy of the Intraaortic Balloon Pump in Cardiogenic Shock II (IABP-SHOCK II) trial. Crit Care 2014;18:713.
Nowak KL, Bartz TM, Dalrymple L, et al. Fibroblast Growth Factor 23 and the Risk of Infection-Related Hospitalization in Older Adults. J Am Soc Nephrol 2017;28:1239-46.
Rodelo-Haad C, Santamaria R, Muñoz-Castañeda JR, Pendón-Ruiz de Mier MV, Martin-Malo A, Rodriguez M. FGF23, Biomarker or Target? Toxins (Basel) 2019;11.
Shimada T, Kakitani M, Yamazaki Y, et al. Targeted ablation of Fgf23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 2004;113:561-8.
Search Suggestions

Search Suggestions

Based on your current searches we recommend the following search filters.



FindAPhD. Copyright 2005-2020
All rights reserved.