Unravelling the role of P4HB in skeletal development: towards treatment of heritable bone fragility

Osteogenesis Imperfecta (OI) affects 1 in 15-20,000 live births and results in a childhood with frequent fractures, reduced mobility and joint problems. Bones and joints are predominantly composed of type 1 collagen which provides a strong framework for these tissues. OI is usually caused due to a problem with type 1 collagen production and/or processing. This condition can have a huge impact on patients and families due to child protection proceedings, recurrent hospital admissions with fractures and surgical procedures.

The overarching aim of this project is to understand how faults in the protein secretion machinery cause OI with a focus on Cole-Carpenter Syndrome-1 (CCS1). We will use zebrafish models to understand how it works in disease; and test drug candidates to see if it is possible to reverse the condition and improve bone formation.

A primary outcome would be to understand the way P4HB works and its role in collagen transportation. A zebrafish model for CCS will provide valuable insights into disease aetiology with wider implications for collagen disorders and more specifically, bone fragility disorders due to role of PDIs in human disease. It will also provide an efficient platform for therapeutic drug discovery. Zebrafish disease models have contributed to advances in understanding diverse human diseases.

A secondary outcome from this proposal would be better insights into collagen processing which would be of clear benefit in OI, a far more common disorder and osteoporosis in the elderly which has a huge disease burden.

 Objectives:

1. Characterise a disease-specific fish model for in vivo investigation of p4hb function

2. Evaluate skeletal manifestations and phenotype of p4hb mutant zebrafish model

3. Test druggable targets using screening assays to rescue p4hb activity in mutant fish

Entry Requirements:

Candidates must have a first or upper second class honors degree or significant research experience. In addition, candidates must be self-motivated, have the ability to think independently, use own initiative, have good communications skills and be well-organized including good time management. An MSc or experience in animal modelling, zebrafish work, including cell culture and in vivo studies would be desirable but not essential.

Enquiries:

Interested candidates should in the first instance contact (Dr Balasubramanian, m.balasubramanian@sheffield.ac.uk)

How to apply:

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying

Please clearly state the prospective main supervisor in the respective box and select ‘School of Medicine & Population Health: Oncology & Metabolism’ as the department.

Proposed start date – 1 March 2024