One in three people with depression do not respond to current treatment, and one in three people with depression show evidence of low-grade systemic inflammation – this may not be a coincidence. Emerging evidence implicates low-grade systemic inflammation in the aetiology of depression, but therapeutic advance will depend on identifying and validating immune proteins or pathways that are causally related to illness risk.
We are offering an exciting 4-year PhD studentship which will use cutting-edge genetic epidemiological and clinical trial data to examine the role of inflammation in depression. The student will be based at the MRC Integrative Epidemiology Unit at the University of Bristol (primary host institution), particularly the Immunopsychiatry and Experimental Medicine Programme, which conducts pioneering research into the role of immune system in depression and other mental disorders using population data, genetics and clinical trials. In addition, they will receive training in immunobiology and novel therapeutics from supervisors at the Cardiff University.
This PhD will provide an excellent training opportunity in mental health, genetic and epigenetic epidemiology, biostatistics, immunology, and novel therapeutics, which would be helpful for future career in academia or industry.
Background
Inflammation is implicated in pathogenesis of depression, with circumstantial evidence pointing to a role of the NLRP3 inflammasome pathway (a key component of the innate immune system responsible for the activation of inflammatory responses). For instance, infection is associated with risk of depression. People with depression have higher levels of inflammatory proteins, such as IL-1β, TNF-α, IL-6, CRP, in blood or cerebrospinal fluid compared with non-depressed controls. In rodents, glucocorticoid driven NLRP3 inflammasome activation in hippocampal microglia has been reported to mediate chronic stress-induced depression-like behaviour. Currently, an industry-led randomised controlled trial (RCT) is testing inhibition of the NLRP3 pathway as a potential treatment for depression. However, evidence from humans for a causal role of the NLRP3 inflammasome pathway in depression is scarce.
Aims & objectives
The student will use genetic, inflammatory protein, and depression data from large population samples and from RCTs of immunotherapies in patients with depression and chronic inflammatory disease to examine whether the NLRP3 inflammasome pathway is causally related to depression, and so could be a novel treatment target for the illness.
Methods
Hypothesis 1: NLRP3 inflammasome pathway biomarkers are causally associated with depression. The student will apply Mendelian randomization (MR) analyses to examine whether factors activating the NLRP3 inflammasome pathway (e.g., infection) and constituent/downstream biomarkers of the NLRP3 inflammasome pathway (e.g., caspase-1, IL-1β, IL-18, TNF-α, IL-6) are causally related to depression. MR is a genetic epidemiological approach that uses genetic variants as proxies to interrogate potential causal links between exposure (here, inflammasome related proteins) and outcome (here, depression). Two-sample MR analyses will be carried out using summary statistics from published large-scale genome-wide association studies (GWAS) and epigenome-wide association studies (EWAS).
Hypothesis 2: Immunotherapies improve mood symptoms by decreasing levels/activity of NLRP3 inflammasome pathway proteins. The student will use data from two RCTs of immunotherapies, which are testing the effects of anti-IL-6R drug tocilizumab and anti-TNF drug infliximab in patients with depression and inflammatory disease, to examine whether improvement in mood symptoms are mediated by decreased levels/activity of NLRP3 inflammasome pathway proteins.
Feasibility and Support
The MR approach relies on the use of existing GWAS and EWAS for immune proteins and depression, which are already available. There will be ample support to gain expertise in MR methodology and other statistical approaches necessary for the proposed work. The MRC Integrative Epidemiology Unit is an internationally leading centre for development and application of MR in health research. Data from the clinical trials will be available in time for the PhD. The RCT of tocilizumab (Insight study led by Khandaker) is now nearing completion, and the second RCT (led by Harrison) will be complete during the early stages of this PhD.
Significance and Clinical Relevance
The proposed PhD will provide vital evidence regarding causal effects of the NLRP3 inflammasome pathway in depression. The findings will inform the development of larger definitive RCTs testing the efficacy of immunotherapies for depression targeting this pathway, and/or help to explain mechanism of effect of novel immunotherapies currently being tested for depression. The proposed work will contribute to development of new treatment for depression, which will be a major step forward considering that one in three people with the illness do not respond to currently available treatment.
How to apply
Student applications can be made via the GW4 BioMed2 website: https://www.gw4biomed.ac.uk. The closing date for applications is 5pm on Friday, 26th November 2021. Shortlisted applicants will be invited for an informal interview (over the phone, on Skype or Zoom) with the lead supervisor (Prof Golam Khandaker) between Monday 31st January 2022 and Friday 11th February 2022. The formal interviews will be held virtually on the 16th and 17th February 2022.
A GW4 BioMed2 MRC DTP studentship includes full tuition fees at the UK/Home rate, a stipend at the minimum UKRI rate (£15,609 for 21/22), a Research & Training Support Grant (RTSG) valued between £2,000-£5,000 per year and £300 annual travel and conference grant based on a 3.5-year full-time studentship. These funding arrangements will be adjusted pro-rata for part-time studentships.
The GW4 BioMed2 MRC DTP studentships are available to UK, EU and International applicants. The GW4 institutions have all agreed to cover the difference in cost between home and international tuition fees. This means that International candidates will not be expected to cover this cost.
For any informal queries about the studentship, please contact Golam Khandaker ([Email Address Removed]).
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