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The role of Inflammation in treatment-resistant depression


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

There are currently no reliable approaches for correctly identifying which patients with major depressive disorder (MDD) will respond well to antidepressant therapy. Inflammation has now been associated with development of depression, however, whether inflammation is causal to antidepressant non-response is unknown. Inflammation, is directly regulated by tumor necrosis factor (TNF) signaling1, a pleiotropic cytokine with important functions in immune homeostasis and immune-disease pathogenesis. TNF increases other pro-inflammatory cytokines including interleukin-6(IL-6) and C Reactive Protein (CRP). Although a common variant in the TNF gene (TNF -308; rs1800629 G>A) is associated with the risk of several common diseases including depression, with the GG allele conferring protection to immune-mediated illnesses, the variant’s exact effect on TNF signaling is not exactly known. Understanding the exact role TNF plays in depression and in particular to antidepressant non-response could highlight targets for prevention and treatment strategies.

Hypothesis and aims

The main hypothesis of this project is that inflammation as measured by disturbed TNF signalling is implicated in depression which could be used as a target for prevention.

The specific research questions we would like to address are:
1- Is the TNF locus circa rs1800629 associated to recurrent major depression and to antidepressant non-response risk factors (obesity, neuroticism, medical illnesses, and lifetime traumatic experiences, self-harm)?
2- What is the exact pathway by which TNF locus circa rs1800629 regulates TNF signalling?
3- Which of the TNF signalling mechanism is dysregulated in patients with major depression?

Main methodologies
For the third part of this project, we will identify recurrent major depression and antidepressant non-response risk factors individuals from the UK Biobank (UKBB) cohort which comprises ~ 500,000 participants aged 40 to 69 years at baseline, and followed up for a variety of mental and physical health conditions. For the second part, online genetics databases such as HaploReg and GTeX will be used to expand the investigation of this associated variant to assess all variants in linkage disequilibrium within the region, annotating them, and seeing which variants express which genes in which tissues, to help pinpoint the most likely causal variants and genes involved. The tissue-specific functionality of TNF and any allelic variation will also be explored using both publicly-available and published Epigenomic Data (ENCODE, Roadmap, Blueprint4, TwinsUK etc.)” Subsequently, using 30 samples from healthy donors we will evaluate detailed functional transcriptomic and epigenomic evaluation of the TNF locus and LD block and biological pathways in samples discordant by genotype. To answer the third question, in collaboration with Prof. F. Rohricht from East London Mental Health Trust we will recruit 30 patients with major depression and analyse the regulation of TNF signalling and compare that to healthy controls.

The legacy of this knowledge would be:
i) To elucidate regulation of TNF signalling which is causally relevant to several complex diseases
ii) To identify mechanisms for new approaches to target TNF axis and anticipate differences in treatment response to TNF therapies based on this common TNF variant.

This project is designed to be a discovery sample in an observational cohort with a proof of concept study. If successful, it will leverage mechanisms targeting TNF as a strategy for prevention and treatment.

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.

Informal enquiries can be made to via email:
Dr. L Carvalho
Prof. K. Bhui,

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.

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