2025-26 Project (Sofat & Chikh & Westaby)

Unravelling novel signalling pathways for inflammation in osteoarthritis development and pain

SUPERVISORY TEAM

Supervisor

Professor Nidhi Sofat at City St George’s
Email: nsofat@sgul.ac.uk

Co-Supervisor

Dr Anissa Chikh at City St George’s
Email: achikh@sgul.ac.uk

Co-Supervisor

Dr Joseph Westaby at City St George’s
Email: jwestaby@sgul.ac.uk

PROJECT SUMMARY

Project Summary

Osteoarthritis (OA) is a degenerative disease that causes joint to become painful and stiff. It is considered as the most common type of arthritis in the UK, with an estimated 10 million of people. We have an exciting opportunity for a PhD to work on a multidisciplinary project investigating the underlying mechanisms of tissue damage, inflammation and pain. This PhD will combine several biological approaches including transcriptomics, human tissue biopsies, biochemistry and cellular biology. The PhD candidate will generate evidence on the molecular mechanisms of cross-talks between tissues during the development of OA and will identify the cellular pathways involved in mediating pain and tissue damage. This work may also open up new avenues for therapeutic strategies in OA.

Project Key Words

Pain, neurobiology, arthritis, bone, cartilage, signalling

MRC LID Themes

  1. Translational and Implementation Research

Skills

MRC Core Skills

  1. Interdisciplinary skills
  2. Quantitative skills
  3. Whole organism physiology

Skills we expect a student to develop/acquire whilst pursuing this project

The student will develop expertise on investigating cellular mechanisms associated to arthritis. Moreover, the student will acquire interdisciplinary skills with:  
– Cell culture, cellular biology and molecular biology including small interfering RNA (siRNA), Enzyme Linked ImmunoSorbent Assay (ELISA), apoptosis assay, migration assay, qRT-PCR, western blotting, immunostaining, digital image analysis, management of complex datasets, statistical analysis.  
– Live cell microscopy, confocal microscopy, histology. 

Overall, the project will allow the student to acquire translational skills that they could apply to several research paths in the future.

Routes

Which route/s are available with this project?

  • 1+4 = Yes
  • +4 = Yes

Possible Master’s programme options identified by supervisory team for 1+4 applicants:

  • City St George’s – MSc Applied Biomedical Science
  • City St George’s – MSc Genomic Medicine
  • City St George’s – MSc Global Health, Infection and Immunity
  • City St George’s – MRes/MSc Translational Medicine

Full-time/Part-time Study

Is this project available for full-time study? Yes
Is this project available for part-time study? Yes

Location & Travel

Students funded through MRC LID are expected to work on site at their primary institution, meeting – at the minimum – the institutional research degree regulations and expectations. Students may also be required to travel for conferences (up to 3 over the duration of the studentship), and for any required training (for research degree study). Other travel expectations and opportunities highlighted by the supervisory team are noted below.

Primary location for duration of this research degree: City St George’s, London

Travel requirements for this project: The student will travel to Epsom and St Helier Hospital for human tissue collection. There will be collaboration with Royal Veterinary College on mouse models of osteoarthritis. Opportunity to observe interviews and surgery for patients with osteoarthritis at St George’s University Hospitals NHS Trust.

Eligibility/Requirements

Particular prior educational requirements for a student undertaking this project

  • Minimum City St George’s institutional eligibility criteria for doctoral study.
  • Master’s degree, or BS in Biomedical Science or Genomics   
  • Previous experience in basic laboratory skills is preferable

Other useful information

  • Potential Industrial CASE (iCASE) conversion? = No

PROJECT IN MORE DETAIL

Scientific description of this research project

Osteoarthritis (OA) is the most common type of arthritis in the UK and worldwide about 600 million people. The exact causes of OA are not known but a certain of risks factors including joint injury, age, family history, obesity and sex are associated in the development of OA. OA patients are suffering from pain and disability due to this condition. Although OA affects large weight bearing joints including the hip and knee, it can also affect the hands. We have recently shown that bone marrow lesions (BML) are a major source of pain in knee osteoarthritis, demonstrating features of angiogenesis and new nerve formation.  The inactive rhomboid protein 2 (iRHOM2) is a proteolytically inactive member of the seven transmembrane family of Rhomboid serine proteases. iRHOM2 can control activation and trafficking of ADAM17 (also known as TACE; TNFα converting enzyme) from the endoplasmic reticulum to the Golgi and then to the cell surface. ADAM17 is a membrane-anchored metalloprotease with a wide range of substrates including cytokines (TNFα), many receptors (IL-6R, TNFR), growth factors (TGFα, AREG) and adhesion proteins. These downstream molecules play key roles in several inflammatory conditions.   

iRHOM2 has also been linked to innate immunity via its regulation of the STING pathway, by mediating the trafficking and stability of the immune adapter protein STING, thereby regulating the broader cGAS-STING pathway and its downstream antiviral genes such as induction of type I interferons and pro-inflammatory cytokines. Accordingly, iRHOM2 is a major regulator of immunity and inflammation. It has been shown that iRHOM2-deficient mice are protected from models of inflammatory arthritis and lupus nephritis.  

We have contributed to the discovery that iRHOM2 is a target gene of the p53-related protein p63 and that together they regulate inflammation, cell survival and response to oxidative stress. In addition, it has been shown that p63 is involved in chondrocyte survival in articular cartilage. In addition, iRHOM2 is involved in the regulation of CSF1R (macrophage stimulating factor 1 receptor), an essential regulator of osteoclast differentiation and survival, and neuroinflammation. Therefore, iRHOM2 may play a role in OA and the dissection of its signalling pathways may reveal key therapeutic targets. 

The objectives of this PhD project are:    
1- To define the signalling pathways involved in bone marrow lesions (BML), synovium and cartilage by cellular studies through genetic manipulation of iRHOM2. 
2- To investigate the expression profile of candidate proteins in human tissue samples.  
3- To establish pharmacologic treatments of candidate markers using small molecules/inhibitors in vitro.   

Accordingly, cells will be depleted for iRHOM2, and RNA-sequencing analysis will be performed to identify molecular signatures gene networks. The identification of transcriptomic profiles and molecular markers will be validated by functional studies.   

Thus, the techniques used will include cell culture, siRNA, overexpression, ELISAs, qRT-PCR, western blotting, apoptosis assay, cell proliferation, migration assay, immunocytochemistry, confocal microscopy, live cell imaging, immunohistochemistry and tissue histology. 

A variety of cell lines (chondrocytes, osteoblasts and osteoclasts) are available. Human tissue source from joint replacement surgeries is available under Ethical Approval for this project.

Further reading

Relevant preprints and/or open access articles:
(DOI = Digital Object Identifier)

Additional information from the supervisory team

The supervisory team has provided a recording for prospective applicants who are interested in their project. This recording should be watched before any discussions begin with the supervisory team.

Sofat-Chikh-Westaby recording

MRC LID LINKS

Comments are closed.