Endocytosis in joint health and disease

Description

Osteoarthritis (OA) is the most prevalent age-related joint disorder that causes pain and disability. Over 8 million people suffer from OA in the UK alone, but there are no disease-modifying drugs available. This is mainly due to insufficient knowledge of molecular events associated with OA progression. 

The hallmark of OA is loss of articular cartilage, which results in impairment of joint function. Our previous studies have shown that the cell surface scavenger receptor, low-density lipoprotein receptor-related protein 1 (LRP1) plays a vital role in maintaining healthy cartilage by removing cartilage matrix-degrading enzymes from the tissue and degrading them in the cell1-3. However, in OA cartilage, the function of the LRP1 receptor is largely lost, because it is proteolytically removed from the cell surface4. This causes accumulation of numerous molecules that are otherwise rarely detectable in healthy cartilage, resulting in tissue damage and cell death in healthy cartilage, leading to OA. 

In this PhD proposal, we aim: 1) to investigate functions of LRP1 ligands with respect to OA pathogenesis and; 2) to delineate the critical role of LRP1 in OA pathogenesis by using a mouse model of OA. Accomplishment of these aims will reveal a novel pathogenic pathway of OA and may allow us to find new avenues for OA therapy. 

The project will provide the student with skills in techniques such as cell culture, recombinant protein purification, protein chemistry, biochemistry and molecular biology. The student will attend Home Office training to obtain a licence to conduct in vivo work including the state-of-the-art in vivo µCT analysis. This will be followed by dissection and histological examination of lung tissue. The student will also learn mass-spectrometry techniques and data analysis skills. Additional skills in literature searching, scientific writing and presentation skills will be gained through the generation of written reports and regular presentations at supervisory meetings. The successful applicant will be encouraged to apply for conference bursaries and awards and attend relevant conferences. 
The Institute of Ageing and Chronic Disease is fully committed to promoting gender equality in all activities. In recruitment we emphasize the supportive nature of the working environment and the flexible family support that the University provides. The Institute holds a silver Athena SWAN award in recognition of on-going commitment to ensuring that the Athena SWAN principles are embedded in its activities and strategic initiatives. 

Potential applicants are encouraged to contact Dr Kazuhiro Yamamoto () in the first instance for an informal discussion. 

The project is suited to a student with an undergraduate degree or Master’s degree in Life Sciences (Biology, Genetics, Biochemistry, Biomedical Sciences, Cell Biology) or Medicine with an interest in extracellular matrix and cellular trafficking. 

Availability

Open to students worldwide

Funding information

Self-funded project

PLEASE NOTE: there is NO funding attached to this project. Details of costs can be found on the University website. The successful applicant will be expected to provide the funding for tuition fees and living expenses plus approximate research costs (bench fees) of approximately £10,000 per year. 

Supervisors

References

1. Yamamoto K, Troeberg L, Scilabra SD, Pelosi M, Murphy CL, Strickland DK and Nagase H. LRP-1-mediated endocytosis regulates extracellular activity of ADAMTS-5 in articular cartilage. (2013) FASEB J, 27, 511-521. 
2. Yamamoto K, Owen K, Parker AE, Scilabra SD, Dudhia J, Strickland DK, Troeberg L and Nagase H. Low-density lipoprotein receptor-related protein 1 (LRP1)-mediated endocytic clearance of a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS)-4: Functional differences of non-catalytic domains of ADAMTS-4 and ADAMTS-5 in LRP1 binding. (2014) J Biol Chem, 289, 6462-6474. 
3. Yamamoto K, Okano H, Miyagawa W, Visse R, Shitomi Y, Santamaria S, Strickland DK, Hirohata S and Nagase H. MMP-13 is constitutively produced in human chondrocytes and co-endocytosed with ADAMTS-5 and TIMP-3 by the endocytic receptor LRP1. (2016) Matrix Biol, 56, 57-73. 
4. Yamamoto K, Santamaria S, Botkjaer K, Dudhia J, Troeberg L, Itoh Y, Murphy G and Nagase H. Inhibition of shedding of low-density lipoprotein receptor-related protein 1 reverses cartilage matrix degradation in osteoarthritis. (2017) Arthritis Rheumatol, 69(6), 1246-1256. 

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