Research Fellow - Inflammation and Ageing

Position Details

• Institute of Inflammation and Ageing
• Full time starting salary is normally in the range £30,942 to £40,322, with potential progression once in post to £42,792
• Grade 7
• Full Time
• Fixed Term Contract Until 31st May 2025

Job Summary

The lab of Dr Adam Croft is looking for a highly motivated and proactive computational biologist. Our research is focused on understanding the cellular and molecular basis of immune mediated inflammatory diseases using systems-level approaches.

We have an exciting opening for a talented scientist to join our group and lead the computational investigation of the cellular basis of treatment refractory rheumatoid arthritis (RA). The research will involve the use of cutting-edge statistical and machine learning approaches to model high-dimensional and multi-modal single-cell genomics datasets. The aim of the project is to discover the cells, inter-cellular signalling circuits, biological pathways and gene regulatory mechanisms that drive the cellular and molecular basis underlying treatment failure and the development of treatment refractory disease. This project is an extension of our previous work using single cell transcriptomics to define pathogenic subsets of fibroblasts in inflammatory arthritis (Croft et al Nature, 2019).

The successful applicant will join an enthusiastic team of scientists and academic clinicians and will be expected to work in close collaboration with the Birmingham Genomics Centre (Dr Andrew Beggs), Kennedy Institute for Rheumatology Research in Oxford (Profs Chris Buckley and Mark Coles) and the Broad Institute in Boston (Prof Michael Brenner). Therefore whilst the primary focus of the applicants research will be the analysis of complex datasets generated from the patient biopsies from patients with RA, the successful applicant will also have the opportunity to contribute to the human cell atlas and collaborate on a large number of ongoing projects.

You should have a successful track record in academic research that includes the statistical analysis and interpretation of complex genomic datasets, excellent problem-solving abilities and a strong interest in inflammatory disease research. A PhD/DPhil (or near completion) in a discipline of direct relevance to computational single cell genomics research is essential. In this role you will perform scientific research, reviewing and refining working hypotheses and developing and acquiring relevant skills as necessary. You will analyse and interpret data, preparing and publishing your findings in peer-reviewed journals. Experience with the analysis of single-cell RNA-sequencing data is desirable. The successful applicant will be based in the Rheumatology Research Group within the Institute of Inflammation and Ageing at the University of Birmingham.

Please read the accompanying job description carefully and ensure that you address each selection criteria in a supporting statement which must be uploaded together with your CV when applying online. For further information please contact Dr Adam Croft: a.p.croft@bham.ac.uk. This is a fixed-term, full-time position for 5 years.

Job Purpose

The Rheumatology Research Group in Birmingham (RRG)

Our group is within the RRG which itself sits within the Institute of Inflammation and Ageing, one of seven research institutes in the College of Medical and Dental Sciences at the University of Birmingham. The RRG is a multidisciplinary team of academic and clinical rheumatologists, biological and social scientists, general practitioners, allied health professionals and patient representatives. Truly collaborative on a global scale, the world-leading RRG research focusses on understanding the epidemiology, mechanisms and pathobiology of three major autoimmune rheumatic diseases; Rheumatoid Arthritis (RA), Systemic Lupus Erythematosus (SLE) and Sjogren's Syndrome (SS). The RRG currently has over £10 million of live funding, from Arthritis Research UK, the Medical Research Council, the Wellcome Trust, NIHR, European Commission and several hospital trusts and industry. The vast range of RRG fundamental science expertise includes stromal cell and immune pathobiology, metabolomics in rheumatic disease and developing animal models of rheumatic disease. The RRG is supported by a £12M NIHR Biomedical Research Centre (BRC) in Inflammation specifically focused on the Inflammatory Arthritis theme within the Centre. The overarching aim of the Inflammatory Arthritis theme is to improve clinical outcomes for those with, and at risk of developing, rheumatoid arthritis (RA) and Sjogren's syndrome (SS) by developing diagnostic tests, drugs and novel therapies to predict, prevent and reverse disease pathology. The NIHR BRC works closely with the £7m Kennedy Trust funded Arthritis Therapy Acceleration Programme (A-TAP) that links Birmingham centres with Oxford along the M40 corridor to develop and accelerate early phase trials of new therapeutics in rheumatological diseases.

Research into Inflammatory Arthritis Centre funded by Versus Arthritis

We are also part of the Rheumatoid Arthritis Pathogenesis Centre of Excellence a partnership between the Universities of Oxford, Glasgow, Birmingham and Newcastle (RACE; http://www.race-gbn.org/) and the fellow will benefit from the collective expertise across the centres.

The research context

Rheumatoid arthritis (RA) is a chronic immune mediated inflammatory disease that is characterized by persistent synovial joint inflammation leading to progressive joint damage1-3. Whilst the introduction of biological disease modifying anti-rheumatic drugs (bDMARDs) targeting either leucocytes or their derived products has led to a step change in the management of RA, 30-40% of patients do not respond to such therapies, regardless of the mechanism of action of the drug used4-8. These observations suggest the existence of additional pathways of disease persistence that remain to be identified and therapeutically targeted9. A significant proportion of patients also develop bDMARD refractory disease over time and these patients represent a significant clinical challenge10. The molecular and cellular basis of refractory disease is poorly understood and research strategies to address this area of unmet clinical need are urgently required.

Whilst significant research has focused on the role of leucocytes in the pathogenesis of RA, much less prominence has been given to the stromal tissue microenvironment, in particular the role of fibroblasts12. We have recently characterized the immune effector functions of synovial fibroblasts during inflammatory arthritis and demonstrated the presence of novel, disease associated, anatomically distinct fibroblast subsets with non-overlapping effector cell functions (inflammation and damage)13,14. Our work has demonstrated that pathogenic fibroblast subsets have an immune effector role and modulate the synovial microenvironment in such a way as to drive the persistent accumulation of leucocytes into the joint, during inflammation. These immune effector fibroblast subtypes are highly enriched in the inflamed RA synovium compared to Osteoarthritis (OA)14.

Kennedy Trust for Rheumatology Research program into treatment refractory RA The post has been generated to support a 2.5M pound senior clinical research fellowship awarded to Dr Adam Croft for a 5-year research programme aimed at understanding the cellular and molecular mechanism underlying treatment refractory RA. The fellow will join a small focused and highly driven team of scientists and clinical academics focused on delivering this programme of research.

In this project, we will test the hypothesis that specific subsets of fibroblasts are the primary immune effector cells that drive the persistence of inflammation in treatment refractory RA, and that the development of a specific 'fibroblast pathotype' (defined as specific composition of fibroblast subset types within the synovial membrane) contributes to treatment failure and the development of refractory disease. More specifically, we propose that changes in the proportion and phenotype of fibroblast subsets are critical modulators of the local inflammatory infiltrate within the joint. We will define the 'fibroblast pathotype' associated with treatment response versus treatment failure and development of refractory disease correlating these findings to functional analysis of these subsets in experimental arthritis in mice. Finally, we will determine the gene regulatory pathways underlying the heterogeneity of fibroblast subsets and changes in their phenotype during inflammatory states and attempt to modulate these pathways with gene silencing techniques.

In summary our objectives are to:

1. Define the 'fibroblast pathotype' associated with the development of refractory disease (multiple treatment failures) by exploring the changes in fibroblast subsets (phenotype, proportion and location) in order to determine the functional consequences of these changes in relation to inflammation, damage and treatment response.

2. Determine the immune effector function of individual fibroblast subsets in inflammatory states in vivo, using mouse models of experimental arthritis to understand the mechanisms by which inflammation persists in some individuals despite treatment.

3. Determine the transcriptional and signalling networks that drive specific programs of gene expression in fibroblast subsets during inflammatory versus resting states in experimental arthritis and disrupt these networks using gene silencing technology such as CRISPR based gene editing to modulate fibroblast phenotype and function.

Main Duties and Responsibilities

These key tasks are not intended to be exhaustive but simply highlight a number of major tasks which the staff member may be reasonably expected to perform.

• To perform scientific research, reviewing and refining working hypotheses, and developing and acquiring relevant skills.
• To analyse and interpret data, preparing and publishing your findings in peer-reviewed journals.
• To actively participate in the broader research team, working closely with clinical and experimental colleagues to share data and findings and help design experiments.
• To communicate results in regular meetings, by poster and oral presentations at scientific meetings, or via other suitable means.
• To write and maintain software pipelines and programs, adapting existing and developing new scientific methods for data analysis.
• To identify training needs and to follow an agreed strategy to meet them.
• To act as a source of information and advice to other members of the group, training and supervise graduate and undergraduate students as appropriate.
• To keep abreast of the relevant literature and methodological developments and to contribute ideas for new research projects.
• To maintain, curate and disseminate the single cell genomics data, submitting it to online databases such as e.g. the Human Cell Atlas data portal as appropriate.
• To manage own academic research and administrative activities. This involves small scale project management, to co-ordinate multiple aspects of work to meet deadlines.

Person Specification

Essential selection criteria

• A successful track record with the statistical analysis and interpretation of complex genomic data sets.
• A PhD/DPhil (or near completion) in a discipline of direct relevant to computational single cell genomics research.
• Degree-level training in cellular and molecular biology/immunology or equivalent experience.
• A passion for problem-solving and research in the areas of genomics and single-cell biology that is grounded in expert-level knowledge or experience.
• Strong competence with the programming language Python and with the statistical language R.
• Highly motivated and able to use own initiative to solve problems.
• Excellent interpersonal skills, able to work independently and collaboratively.
• Excellent communication skills, both oral and written.
• Excellent organisational and project management skills, able to manage both time and
• records effectively.
• Good working knowledge of office software.
• Demonstrate an ability to follow departmental guidance in handling sensitive and
• personal information, including complying with current data protection legislation

Desirable selection criteria

• Strong publication track record and experience of presenting work at meetings.
• Experience with the analysis of single-cell RNA-sequencing data.
• Cross-disciplinary collaborative experience.

For informal queries please contact Dr Adam Croft ( A.P.Croft@bham.ac.uk )

Further particulars can be found here

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