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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
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Overview

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.

About this opportunity

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is documented in very few studies [2,4-5] and a handful of case reports, in addition to tendon calcification (Hughes, unpublished). Unpublished data from Dr Hughes’ lab provides preliminary evidence that pigmented tendon has altered biomechanical properties.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.

Further reading

[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/

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Who is this for?

Undergraduate or master’s level degree in a biological science, anatomy or veterinary studies

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How to apply

  1. 1. Contact supervisors

    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
  2. 2. Prepare your application documents

    You may need the following documents to complete your online application:

    • A research proposal (this should cover the research you’d like to undertake)
    • University transcripts and degree certificates to date
    • Passport details (international applicants only)
    • English language certificates (international applicants only)
    • A personal statement
    • A curriculum vitae (CV)
    • Contact details for two proposed supervisors
    • Names and contact details of two referees.
  3. 3. Apply

    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).

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Fees and funding

Your tuition fees, funding your studies, and other costs to consider.

Tuition fees

UK fees (applies to Channel Islands, Isle of Man and Republic of Ireland)

Full-time place, per year - £5,006

International fees

Full-time place, per year - £31,249

Fees stated are for academic year 2025/26


Additional costs

We understand that budgeting for your time at university is important, and we want to make sure you understand any costs that are not covered by your tuition fee. This could include buying a laptop, books, or stationery.

Find out more about the additional study costs that may apply to this project, as well as general student living costs.


Funding your PhD

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.

There’s also a variety of alternative sources of funding. These include funded research opportunities and financial support from UK research councils, charities and trusts. Your supervisor may be able to help you secure funding.


We've set the country or region your qualifications are from as United Kingdom.

Scholarships and bursaries

We offer a range of scholarships and bursaries that could help pay your tuition fees and living expenses.

Duncan Norman Research Scholarship

If you’re awarded this prestigious scholarship, you’ll receive significant funding to support your postgraduate research. This includes full payment of your PhD fees and a cash bursary of £17,000 per year while you study. One award is available in each academic year.

John Lennon Memorial Scholarship

If you’re a UK student, either born in or with strong family connections to Merseyside, you could be eligible to apply for financial support worth up to £12,000 per year for up to three years of full-time postgraduate research (or up to five years part-time pro-rata).

Sport Liverpool Performance Programme

Apply to receive tailored training support to enhance your sporting performance. Our athlete support package includes a range of benefits, from bespoke strength and conditioning training to physiotherapy sessions and one-to-one nutritional advice.

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Contact us

Have a question about this research opportunity or studying a PhD with us? Please get in touch with us, using the contact details below, and we’ll be happy to assist you.

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