Establishing the Insulin-like growth factor 1 (IGF-1) axis as a therapeutic target in carpal tunnel syndrome and trigger finger

project overview

Carpal tunnel syndrome (CTS) is a very common and disabling condition of the hand caused by compression of the median nerve as it travels through a bony tunnel in the wrist. It affects up to 10% of the population, and carpal tunnel decompression surgery is the most commonly performed elective hand operation worldwide. However, up to 25% of patients do not improve, or develop recurrent symptoms following surgery.

CTS is a typical complex disease, where genetic and non-genetic factors interact to affect overall phenotypic expression. We previously performed the first ever genome-wide association study (GWAS) of CTS, and identified 16 loci in the genome significantly associated with the disease, discovering a biologically plausible set of genes that contribute to CTS pathophysiology. In a subsequent study, we identified the Insulin-like growth factor 1 (IGF-1) axis as a driver of CTS pathophysiology. Our hypothesis is that overactivity of the IGF-1 pathway leads to fibrosis and proliferation of the sub-synovial connective tissues (SSCT), which are the connective tissues that surround the median nerve and the flexor tendons within the carpal tunnel. This fibrosis, in turn, causes tethering of the median nerve to surrounding structures, leading to nerve ischaemia and eventually nerve degeneration.

There are currently no effective drug treatments for CTS. The overarching aim of this DPhil project is to determine whether drugs that target the IGF-1 axis can be used in the treatment of CTS. Demonstrating, in vitro, that IGF-1 downregulation in the SSCT can reduce this tissue's propensity towards proliferation and fibrosis will demonstrate the proof-of-principle that the IGF-1 axis may be a viable therapeutic target in CTS patients.

In this project, the student will use the combined expertise of the supervisory team to
(i) Characterise the cellular and connective tissue microenvironment of the median nerve within the carpal tunnel using a combination of single-cell RNA sequencing and advanced imaging techniques.
(ii) Characterise where the IGF-1 receptor and its binding proteins are expressed within the SSCT.
(iii) Compare the expression of these genes and proteins between SSCT resected from CTS patients and healthy controls.
(iv) Study the functional effects of up- and down-regulation (using small molecule inhibitors/monoclonal antibodies) of the IGF-1 pathway on cultured fibroblasts derived from the SSCT.

The student will be trained in a broad spectrum of experimental techniques, including (but not limited to) single-cell RNA sequencing, bulk-RNA sequencing, genotyping and qPCR, Western blotting, cell culture, confocal microscopy, and immunohistochemistry. There will also be training in advanced data analytics for processing and analysing the transcriptomic data. Furthermore, the student will gain valuable experience of a study involving human participants, including gaining a good grounding in research ethics, obtaining informed consent from participants, and collecting, processing and storing human tissues in accordance with the Human Tissue Act.

This is an exciting project that spans the translational medicine pipeline, and builds on existing collaborations between plastic surgeons, rheumatologists, and laboratory scientists. It is hoped that characterising and establishing the IGF-1 axis as a viable therapeutic target in the SSCT will form the foundations of a future experimental medicine human trial of anti-IGF-1 therapies in CTS patients.

keywords

IGF-1, Single Cell Sequencing, Transcriptomics, Carpal Tunnel Syndrome, Nerve Injury

training opportunities

The Botnar Research Centre plays host to the University of Oxford's Institute of Musculoskeletal Sciences, which enables and encourages research and education into the causes of musculoskeletal disease and their treatment. The student will also be partly based in the modern building and laboratories of the Kennedy Institute of Rheumatology, a world-leading centre in the fields of cytokine biology and inflammation, with a strong emphasis on clinical translation.

A core curriculum of lectures will be taken in the first term to provide a solid foundation in a broad range of subjects including musculoskeletal biology, inflammation, epigenetics, translational immunology, data analysis and the microbiome. All students are required to attend a two-day Statistical and Experimental Design course at NDORMS. The student will attend regular seminars within the department and those relevant in the wider University.

The student will receive training in relevant related research methodologies including cell culture, immunohistochemistry, molecular techniques, flow cytometry, and the handling and analysis of single cell sequencing datasets.

Additional on-the-job training opportunities will arise, and the supervisors will encourage the student to pursue such opportunities. Attendance at formal training courses will be encouraged. In addition, courses from the Oxford Learning Institute and the Oxford University Computer Sciences on generic skills for scientific research will be available and encouraged. Students will be expected to present data regularly in the departmental PGR seminars, Furniss and Vincent group meetings, and to attend external conferences to present their research globally.

key publications

1. Shared genetic susceptibility between trigger finger and carpal tunnel syndrome: a genome-wide association study. Patel B, Kleeman SO, Neavin D, Powell J, Baskozos G, Ng M, Ahmed WU, Bennett DL, Schmid AB, Furniss D, Wiberg A. Lancet Rheumatol. 2022 Aug;4(8):e556-e565. doi: 10.1016/S2665-9913(22)00180-1.PMID: 36043126
2. A genome-wide association analysis identifies 16 novel susceptibility loci for carpal tunnel syndrome. Wiberg A, Ng M, Schmid AB, Smillie RW, Baskozos G, Holmes MV, Künnapuu K, Mägi R, Bennett DL, Furniss D. Nat Commun. 2019 Mar 4;10(1):1030. doi: 10.1038/s41467-019-08993-6.PMID: 30833571
3. Therapeutic Targeting of the IGF Axis. Osher E, Macaulay VM. Cells. 2019 Aug 14;8(8):895. doi: 10.3390/cells8080895.PMID: 31416218
4. Variants in ALDH1A2 reveal an anti-inflammatory role for retinoic acid and a new class of disease-modifying drugs in osteoarthritis Zhu L, Kamalathevan P, Koneva L, Zarebska J, Chanalaris A, Ismail H, Wiberg A, Ng M, Muhammed H, Watt F, The Oxford Hand Surgical Team4, Sansom S, Furniss D, Gardiner M, Vincent T. bioRxiv 3/11/2021. doi: https://doi.org/10.1101/2021.09.10.457848 (in revision)

contact information for all supervisors

Email: dominic.furniss@ndorms.ox.ac.uk, tonia.vincent@kennedy.ox.ac.uk, valentine.macaulay@nds.ox.ac.uk, akira.wiberg@ndorms.ox.ac.uk