Tendons Under Attack: The Role of Homogentisic Acid in Connective Tissue Degeneration
- Funding
- Self-funded
- Study mode
- Full-time
- Apply by
- Year round
- Start date
- Year round
- Subject area
- Biological and Biomedical Sciences
This PhD project explores how a rare disease - Alkaptonuria - damages tendons, offering unique insights into oxidative stress and tissue degeneration. Using various tendon models, it aims to uncover mechanisms behind pigmentation, rupture, and repair, with implications for both rare and common tendon disorders.
Background
Tendons and ligaments are essential components of the musculoskeletal system, formed of dense connective tissue. Tendinopathy is a degenerative process in which tendons become inflamed and painful and can lead to rupture. Alkaptonuria (AKU) is an example of a rare genetic, degenerative condition in which the body tissues are exposed to a pathological metabolite called homogentisic acid (HGA) that circulates in the blood. In AKU, HGA-derived pigment deposits in connective tissues across the body with a high affinity for cartilage [1], but also includes tendon, ligament and blood vessels. AKU individuals consistently develop osteoarthritis and are also prone to spontaneous tendon and ligament rupture [2].
Due to joint arthropathy being so severe, the tendon disease that manifests in AKU is understudied. AKU mice are limited to early-stage cartilage pigmentation, with no evidence of tendon or ligament pigmentation, except within the enthesis [3]. Tendon pigmentation and rupture is documented in very few studies [2,4-5] and a handful of case reports, in addition to tendon calcification (Hughes, unpublished). Unpublished data from Dr Hughes’ lab provides preliminary evidence that pigmented tendon has altered biomechanical properties. Recently there is also a growing body of evidence that oxidative stress is a major part of AKU disease pathophysiology. The Liverpool AKU Research Group has shown that HGA is undergoes auto-oxidation and that HGA-pigment is a source of free-radicals, and that antioxidant pathways are markedly altered in AKU biofluids and tissues [6-7].
Objectives
This project aims to study the process of HGA exposure and pigmentation on the biology and function of tendons. To do this, novel in vitro and ex vivo models of AKU tendon will be established and used to study the pathophysiology of tendon disease. Although collagen is suspected as a binding site for HGA, it is unknown where in the extracellular matrix HGA binds, and how it causes degenerative changes, tendinopathy, calcification, and rupture. In addition to AKU tendinopathy, the unique properties of HGA also provide the opportunity to study the effect of oxidative stress on tendon biology.
Aim 1: Establish in vitro and ex vivo models of tendon with and without HGA exposure.
Aim 2: Determine the effect that HGA has on tendon biology and function.
Aim 3: Assess reactive oxygen species (ROS) production, mitochondrial health and redox balance in HGA-treated tendon models.
Experimental approach
This project will encompass a range of skills and techniques including tissue culture (2D, 3D and explant culture) [8], biomechanical testing, histology and omics. Students from related fields (e.g., molecular biology, bioengineering, oxidative stress, cell biology) are welcome and training will be provided.
Potential impact
By studying this rare condition, you’ll contribute to knowledge that could benefit AKU patients and also those affected by common tendon disease. By studying what goes wrong in a rare disease, key biological pathways can be studied and mechanisms often shared with more common diseases can be uncovered. The unique properties of the HGA molecule allow the impact of oxidative stress to be studied, as other small molecules likely attack tendon in a similiar way.
[1] Taylor et al. Arthritis Rheum. 2011 Dec;63(12):3887-96. https://pubmed.ncbi.nlm.nih.gov/22127706/
[2] Phornphutkul et al. N Engl J Med. 2002 Dec 26;347(26):2111-21. https://pubmed.ncbi.nlm.nih.gov/12501223/
[3] Hughes et al. Calcif Tissue Int. 2021 Feb;108(2):207-218. https://link.springer.com/article/10.1007/s00223-020-00764-6
[4] Helliwell et al. Histopathology. 2008 Nov;53(5):503-12. https://onlinelibrary.wiley.com/doi/10.1111/j.1365-2559.2008.03000.x
[5] Manoj Kumar & Rajasekaran. J Bone Joint Surg Br. 2003 Aug;85(6):883-6. https://pubmed.ncbi.nlm.nih.gov/12931812/
[6] Chow et al. Angew Chem Int Ed Engl. 2020;59(29):11937-11942. https://onlinelibrary.wiley.com/doi/full/10.1002/anie.202000618
[7] Norman et al. Clin Chem. 2019 Apr;65(4):530-539. https://pubmed.ncbi.nlm.nih.gov/30782595/
[8] Janvier et al. J Tissue Eng. 2022 Oct 31;13:20417314221130486. https://pmc.ncbi.nlm.nih.gov/articles/PMC9629721/
Undergraduate or master’s level degree in a biological science, anatomy or veterinary studies
Please send an initial CV and covering letter to Dr Juliette Hughes (jhhughes@liverpool.ac.uk) to express your interest in this project, and for informal enquiries.
| Dr Juliette Hughes | jhhughes@liverpool.ac.uk | https://www.liverpool.ac.uk/people/juliette-hughes |
| Dr Elizabeth Laird | elizabeth.laird@liverpool.ac.uk | https://www.liverpool.ac.uk/people/elizabeth-laird |
| Dr Riaz Akhtar | rakhtar@liverpool.ac.uk | https://www.liverpool.ac.uk/people/riaz-akhtar |
| Professor Eithne Comerford | ejc@liverpool.ac.uk | https://www.liverpool.ac.uk/people/eithne-comerford |
You may need the following documents to complete your online application:
Finally, register and apply online. You'll receive an email acknowledgment once you've submitted your application. We'll be in touch with further details about what happens next.
To apply, please send a covering letter and CV to Dr Juliette Hughes: jhhughes@liverpool.ac.uk . Candidates should specify their funding source.
Candidates will receive an email once their application has been received.
The application will close once a suitable candidate is found.
On the research degree application portal, please refer to the project title and primary supervisor (Dr Juliette Hughes).
Your tuition fees, funding your studies, and other costs to consider.
Full-time place, per year - £5,006
Full-time place, per year - £31,249
Fees stated are for academic year 2025/26 and may be subject to change for academic year 2026/27. The University may administer inflationary rises to international fees in subsequent academic years as you progress through the course.
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No funding is available for this project. It is a self-funded project. Potential applicant will require their own funding for tuition fees, bench fees and living expenses.
If you're a UK national, or have settled status in the UK, you may be eligible to apply for a Postgraduate Doctoral Loan worth up to £30,301 to help with course fees and living costs.
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