Research Fellow - Institute of Inflammation and Ageing

Location
United Kingdom
Salary
£30,942.00 - £42,792.00
Posted
Oct 05, 2020
Closes
Nov 03, 2020
Ref
144136
Organization Type
University and College
Hours
Full Time
Summary of Role

We are looking for a talented and highly motivated scientist to join the lab of Dr Helen McGettrick in the Rheumatology Research Group with the Institute of Inflammation and Ageing. Our research is focused on understanding the cellular and molecular basis of immune mediated inflammatory diseases.

We have an exciting opening for an enthusiastic scientist to join our group and lead on the experimental immunology and molecular biology component of a 3-year translational research project funded by the Medical Research Council. The aim of the project is to investigate the bioactivity of the adiponectin-PEPITEM pathway in human inflammatory arthritis and determine the therapeutic potential of PEPITEM. This research will involve the use of cell culture, molecular biology, specific omics analysis and advanced imaging approaches to define the cellular and molecular mechanisms responsible for inducing and responding to the adiponectin-PEPITEM pathway during inflammatory arthritis. Reporter mouse models will be utilised to define the subsets of leukocyte trafficking into the joint in response to PEPITEM therapy and the local changes in sphingosine-1-phosphate signalling elicited. The latter studies will involve the successful applicant spending time in Dr Susan Schwab's laboratory at New York University. The aim of the project is to discover the cellular and molecular basis by which the adiponectin-PEPITEM pathway modulates the induction, maintenance and resolution of arthritis, and the utility of manipulating the pathway for therapeutic benefit.

The successful applicant will be based in the Rheumatology Research Group within the Institute of Inflammation and Ageing at the University of Birmingham and will join an enthusiastic team of scientists and academic clinicians. You will be expected to work in close collaboration with the Leukocyte Trafficking Group (Professor Ed Rainger and Dr Myriam Chimen), Advanced imaging suite in Birmingham and with our collaborators in the New York University (Dr Susan Schwab) and the RACE consortium.

You will manage your own academic research and administrative activities, this involves small scale project management, to co-ordinate multiple aspects of work to meet deadlines. You will adapt existing and develop new scientific techniques and experimental protocols and test hypotheses and analyse scientific data from a variety of sources, reviewing and refining working hypotheses as appropriate. You will use specialist scientific equipment in a laboratory environment and act as a source of information and advice to other members of the group on scientific protocols and experimental techniques.

You must hold a relevant PhD/DPhil (or near completion), together with relevant experience in standard techniques of immunology and have a demonstrable track record in immunology/stromal cell biology, evidenced by first author publications in high quality, peer-reviewed journals. An understanding of the processes governing leukocyte trafficking in health and disease, and having a personal licence to work with animals in the UK or be prepared to obtain such a licence via attendance of in-house courses is essential. Experience and expertise in leukocyte and stromal cell biology, mouse models of inflammation, basic bioinformatic analysis and interpretation is desirable.

The research context

The inappropriate accumulation and activation of leukocytes is a shared pathological feature of immune-mediated inflammatory diseases (IMIDs), such as rheumatoid arthritis (RA)1 and psoriatic arthritis (PsA)2. Cellular accumulation is therefore an attractive target for therapeutic intervention3,4. However, attempts to target leukocyte accumulation within the joint by modulating their recruitment and retention have not been successful to date5. We have identified a novel immune regulatory pathway, in which a B-cell derived peptide (PEPITEM) limits T-cell trafficking into inflamed tissues6. This pathway is impaired in patients with a range of IMIDs: RA6, type-1-diabetes (TID)6, inflammatory bowel disease (IBD), atherosclerosis, uveitis and multiple sclerosis [unpublished observations], suggesting broad relevance of this regulatory pathway. The situation in PsA is unknown, though notably it shares parallel pathology with IMIDs like uveitis and IBD7. Crucially, synthetic PEPITEM was able to bypass the defect in peripheral blood lymphocytes from patients with RA and T1D to restore the inhibitory effects of the pathway on T-cell migration in ex vivo migration assays6. Furthermore, we now have preliminary data showing that therapeutic administration of PEPITEM significantly reduces disease severity and bone damage in murine models of inflammatory arthritis, potentially by increasing the numbers regulatory leukocyte within the synovium. This leads to the exciting possibility that targeting the adiponectin-PEPITEM pathway represents a valid therapeutic approach for treating a range of IMIDs.

Expanding our understanding of the endogenous regulatory cues controlling leukocyte accumulation will provide novel cellular and molecular mechanistic insights into disease pathology in RA and PsA. This knowledge has the potential to identify patient subgroups based on shared molecular processes driving pathology, as well as identifying innovative therapeutic targets that restore an inhibitory/pro-resolution pathway to turn off recruitment of pathological leukocytes, whilst promoting the entry of regulatory leukocytes. Our strategy aims to open new avenues in the clinical management of RA, PsA and other IMIDs, allowing personalised medicine based on the molecular signature of each patient at a given time point (phase/stage) in the course of their disease.

Medical Research Council Project: New therapeutic avenues in inflammatory arthritis: exploring the role of the adiponectin-PEPITEM pathway

The post has been generated to support a Medical Research Council funded project grant awarded to Dr Helen McGettrick for a 3-year research project aimed at understanding cellular and molecular functionality of the adiponectin-PEPITEM pathway to determine its contribution to disease pathogenesis, and its efficacy as a novel therapeutic tool. 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 impairment of the adiponectin-PEPITEM pathway contributes to pathology in RA and PsA by dysregulating leukocyte recruitment. Moreover, that correction of such dysregulation will confer therapeutic benefits. We will combine studies using both human samples and mouse models of inflammatory arthritis to interrogate the functionality of the adiponectin-PEPITEM pathway in RA and PsA. We will measure changes in the bioactivity of the pathway in RA and PsA at different phases of disease in order to identify pathway-specific disease subtypes. Simultaneously, we will examine the impact of manipulating the adiponectin-PEPITEM pathway in models of inflammatory arthritis to further dissect the cellular and molecular mechanisms of action and determine the therapeutic potential of PEPITEM.

In summary our objectives are to:
  1. Determine the bioactivity of the adiponectin-PEPITEM pathway in patients with rheumatoid arthritis or psoriatic arthritis by exploring the ability of patient derived cells (leukocytes and endothelial cells) to response to the pathway ex vivo and in vitro. This will identify whether molecular or cellular impairments in the adiponectin-PEPITEM pathway are shared by both diseases, and represent a common target for clinical intervention, and also examining patients at different phases of their disease will identify when these molecular or cellular impairments occur and therefore when it would be appropriate to treat patients with a new therapy that restores the pathway.
  2. Determine the effects of PEPITEM treatment on leukocyte and stromal cell subpopulations in vivo, using mouse models of experimental arthritis to understand the cellular and molecular mechanisms by which PEPITEM treatment modulates disease activity.
  3. Characterise the immunoprotective role of PEPITEM induced sphingosine-1-phosphate in vivo, using S1P reporter mice from our collaborators at NYU.


Role overview

The successful applicant will be responsible for leading the experimental immunology, tissue analysis and molecular biology components of the project including functional analysis of leukocyte, endothelial cell and fibroblast subsets from patients with Rheumatoid arthritis and Psoriatic arthritis, as well as from murine models of inflammatory arthritis by e.g. CyTOF, flow cytometry, Advanced Imaging Models or Omics approaches. To achieve these aims you will work in close collaboration with a research technician and PhD student.

Main Duties

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.
  • Develop research objectives and proposals for own or joint research, with assistance of a mentor if required
  • 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 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 manage own academic research and administrative activities. This involves small scale project management, to co-ordinate multiple aspects of work to meet deadlines.


Relationships
  • The Postdoctoral Fellow will be a member of the Inflammation and Stromal Biology Team led by Dr Helen McGettrick at the Institute of Inflammation and Ageing.
  • The post-holder will work closely with clinical and experimental colleagues in the research groups of Professor Karim Raza, Professor Chris Buckley and Dr Andrew Filer.
  • The post-holder will also work with colleagues in the RACE consortium (http://www.race-gbn.org/).


Person Specification

Essential:
  • A personal licence to work with animals in the UK or be prepared to obtain such a licence via attendance of in-house courses is essential
  • A PhD/DPhil (or near completion) in a discipline of direct relevant to immune-mediated inflammatory disease research.
  • Degree-level training in cellular and molecular biology/immunology or equivalent experience.
  • Experience in problem-solving and research in the areas of cell biology, immunology or stromal cell biology that is grounded in expert-level knowledge or experience.
  • A successful track record with the statistical analysis and interpretation of experimental data.
  • 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:
  • Strong publication track record and experience of presenting work at meetings.
  • Cross-disciplinary collaborative experience.


Background

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) and the fellow will benefit from the collective expertise across the centres.

Funding Sources

The post is funded as part of a Medical Research Council Project Grant awarded to Dr Helen McGettrick.

Assessment of Progress

The successful applicant will report directly to Dr Helen McGettrick and will be expected to provide regular reports of their research progress and present their results at regular research in progress meetings within the group and wider institute.

Informal enquires to Dr Helen McGettrick ( h.m.mcgettrick@bham.ac.uk )

We value diversity at The University of Birmingham and welcome applications from all sections of the community '

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