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Comorbidity between Depression and Diabetic kidney Disease – the role of Inflammation (DECODIN)


Project Description

Applications are invited from graduates with a BSc (First or Upper Second) or MSc (Distinction), or equivalent, to work within the Wolfson Institute of Preventive Medicine. This 3 year studentship will commence in Spring 2020 and will be based at the Charterhouse Square Campus. This is an exciting opportunity for a graduate from disciplines related to epidemiology, statistics, and behavioural sciences.

Project description

Introduction
Depression affects up to a third of people treated with diabetes (1). Depression increases the risk of diabetic kidney disease(2) and is a strong predictor of poor prognosis(3). Depression in the physically ill is associated with even higher cardiovascular morbidity and mortality – inflammation might be a common causal link(4, 5). Despite this, it is unclear whether the two diseases have shared underlying mechanisms. Identifying common risk factors between the two diseases would highlight potential shared etiology and suggest joint prevention and treatment strategies.

Hypothesis and aims
The main hypothesis of this project is that depression and diabetic patients have shared disease mechanisms particularly involving the inflammatory system.

The specific research questions we would like to address are:
1- Is the high comorbidity between diabetes and depression due to genetic or to environmental factors?
2- Are risk factors for diabetes causal to the development of depression using Mendelian Randomization?
3- What are the shared underlying mechanisms between these two conditions?

The legacy of this knowledge would be to influence treatment decisions in the discovery of primary or secondary targets for prevention.

Main methodologies
For the first and second part of this project, we will use data from the UK Biobank (UKBB) which comprises ~ 500,000 participants aged 40 to 69 years at baseline, and followed up for a variety of health conditions. Diabetes Mellitus and Major Depression patients will be identified in the UKBB and we will conduct a genome wide association study to identify shared variants that could explain the high comorbidity between these two disorders. For the third part of this project, it will build on an existing and ongoing 3-years study named HEROIC led by Prof. Yaqoob. For the HEROIC Study, paxgene RNA tubes are being collected - but not processed - from 500 CKD patients with confirmed diabetic nephropathy via biopsy from the Barts Renal Unit. For this DECODIN Study, we will extract and process the RNA of selected 12 depressed and 12 non-depressed CKD patients and conduct a high throughput whole-genome gene expression profiling (RNA-seq, Illumina). This will be conducted at the Genome Centre. We will then validate findings using individual qPCR. In collaboration with Prof. Barnes from WHRI, we will then use bioinformatics tools like connectivity map (https://clue.io/cmap) to compare patient-derived gene expression signatures with in-vitro molecular signatures of drug treatment in-vitro. These comparisons may contribute towards prediction of which known anti-inflammatory drug best target pathways that are chronically dysregulated.
This project will not result in duplication of funding. Scientific potential and track record: Dr. LA Carvalho is a Lecturer in Immuno-psychopharmacology at the WHRI and conducts research on the relationship between stress and psychopathology in different clinical populations, using cellular, molecular and epidemiological models. Prof. Magdi Yaqoob is a Professor and Consultant Nephrologist, Renal Unit, Barts Health NHS Trust and Queen Marys University of London, UK Professor Director of Diabetic kidney disease centre, Barts Health NHS Trust and Renal Advisor for BNF.

Informal enquiries can be made to via email: Dr. L Carvalho Dept of Clinical Pharmacology, WHRI
Prof. Magdi Dept of Translational Medicine & Therapeutics, WHRI
Prof. Kam Bhui, Wolfson Institute,

How to apply
Your application should consist of a CV and contact details of two academic referees. You must also include a personal statement (1,000 words maximum) describing your suitability for the selected project including how your research experience and interests relate to the project.

Please submit your application to: Patrick Mullan ().


Funding Notes

This 3 year PhD studentship is funded by the Wolfson Institute of Preventive Medicine and comes with a tax-free stipend of £21,000. It is open to UK Nationals, EEA/Swiss migrant workers and non-UK nationals with indefinite leave to remain in the UK who will have three years ordinary residence in the EU prior to the start of the studentship. University tuition fees (at UK/EU levels) will be met by the Institute.

References

1.Taraz M, et al Hemodial Int. 2015;19(1):11-22.
2.Novak M, et al Diabetes Care. 2016;39(11):1940-7.
3.Young BA, et al. Gen Hosp Psychiatry. 2010;32(2):119-24.
4.Armstrong NM, et al J Aging Health. 2017:898264317744921.
5. Lawes S, et al Psychol Med. 2018:1-11.

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