Targeting Pro-resolving Pathways to Mitigate the Cardiomyopathy of Inflammatory Arthritis Using Human Cells Co-culture System and a Pre-clinical Mouse Model

Project Background: Rheumatoid arthritis (RA) patients do not die from arthritis but from complications associated with this devastating chronic disease, with cardiovascular events causing around half of all deaths in these patients [1]. Compared to the general population, RA patients are over twice as likely to develop heart problems. They are particularly susceptible to a type of heart failure with preserved ejection fraction/contractility (HFpEF) [1]; it is accompanied by diastolic dysfunction, whereby the heart fails to relax and refill fully after each heartbeat. What causes this dysfunction in RA patients is unknown and current medicines do not reduce these heart problems. We have developed an experimental animal model of arthritis, which mirrors the specific heart dysfunction of RA patients [2] and have found the pro-resolving signalling is dysregulated in arthritic hearts.

The aim of this studentship is to i) further our understanding of the dysregulated pro-resolving mechanisms in the heart in concomitance with the heart dysfunction over time; ii) determine the impact of novel pro-resolving strategies on heart dysfunction and joint disease using human cells co-culture systems and a pre-clinical mouse model.

Training/techniques to be provided:

The student will gain a home office personal licence and will be trained in models of arthritis as well as assessment of cardiac function by echocardiography. The project will also involve working with co-culture systems of various human cell types, including cardiomyocytes, and will include a significant component of two-photon confocal macroscopy, multi-colour flow cytometry, RT-PCR and ELISAs, for which full training will be given.

In this project, using a mouse model of arthritis, we can select specific times when i) mice have arthritis but no heart problems, and ii) when heart problems are fully evident. We can analyse whether dysregulated pro-resolving mechanisms are linked to heart inflammation and the development of the diastolic dysfunction. Pro-resolving signalling pathways will be studied using two-photon confocal microscopy, RT-PCR and ELISAs.

Guided by the results from above experiments, a novel pro-resolving treatment that promotes resolution of inflammation will be tested in human cells co-culture systems. It will also be tested in a pre-clinical mouse model where heart function and joint symptoms will be assessed.

Benefits for patients: i) As we will study the association between the dysregulated pro-resolving mechanisms and development of heart problems in RA patients, we hope to identify markers predictive of heart dysfunction to guide early cardiovascular intervention, as well as identify novel therapeutic targets; ii) Elucidation of therapeutic targeting of inflammation may ultimately impact decision making for preventing development of heart failure in RA patients and/or a tailored treatment for patients who have already developed heart problems; iii) Successful reduction/halting of heart dysfunction in RA patients will not only reduce death but will also improve their quality of life.

Benefits for the wider scientific and clinical community: Both human and murine studies indicate existence of a link between diseases associated with inflammation (obesity, diabetes mellitus, chronic kidney disease and inflammatory arthritis) and development of HFpEF; unfortunately the long-term prognosis for HFpEF patients remains bleak. Findings from this project will increase our knowledge on mechanisms of the experimental disease and may offer therapeutic avenues for controlling it.

References

1.    Chen, J., L.V. Norling, and D. Cooper, Cardiac Dysfunction in Rheumatoid Arthritis: The Role of Inflammation.Cells, 2021. 10(4).

2.    Chen, J., et al., Annexin A1 attenuates cardiac diastolic dysfunction in mice with inflammatory arthritis. Proc Natl Acad Sci U S A, 2021. 118(38).

Students Entry Requirements:

Applicants should either be Home or Oversea, and have a good honours degree (minimum 2(i) or equivalent) with a strong background in biomedical science and an interest in cardiovascular based research.

How to apply:

Please send your covering letter (detailing why you would like to apply) and CV to jianmin.chen@qmul.ac.uk.

Further information on the multi-disciplinary science underpinning this research area can be found at www.qmul.ac.uk/citi/.

Deadline for applications: 18^th Nov 2024.

Supervisors names and email addresses:

1) Dr Jianmin Chen. Email address: Jianmin.chen@qmul.ac.uk

2) Prof Mauro Perretti. Email address: m.perretti@qmul.ac.uk

3) Dr Lucy Norling. Email address: l.v.norling@qmul.ac.uk