Precision Therapy for NBAS-related disorder

All faculties are accepting applications for the University of Sheffield Research Scholarships for Black or Black British (of African or Caribbean heritage), Asian or Asian British (of Bangladeshi, Pakistani and Indian heritage) or multiple ethnic background including one of the ethnicity groups listed above. 

The University of Sheffield is committed to increasing opportunities in doctoral research for particular minoritised students who are currently under-represented in our postgraduate research student population.

Candidates will be required to complete a declaration form and upload it to their application.

It is very well recognised that rare diseases offer the potential to uncover new information about mechanisms underlying a range of phenotypes. Mechanistic insights benefit patients suffering from the disease in question, but also provide information with the potential for wider benefit. NBAS mutations causes SOPH syndrome (Short stature; Optic atrophy; Pelger-Huet anomaly), fractures and acute-onset liver failure. Through Sheffield Children’s Hospital Charity funded study to identify new genes in bone fragility, we discovered that mutations in NBAS (Neuroblastoma Amplified Sequence Gene) are responsible for skeletal abnormalities [Balasubramanian et al., 2017]. Majority of patients with NBAS-related disorder have a homozygous recurrent missense variant c.5741G>A,p.Arg1914His.

We have now generated two zebrafish models for nbas and analysed the skeletal phenotype. The next step is to develop a precision therapy for treating this homozygous recurrent missense mutant nbas zebrafish model which is the focus of this project; principles learnt from this proposal can be applied to a wide variety of rare bone diseases including Osteogenesis Imperfecta (OI), the commonest form of heritable bone fragility.

The nbas mutant fish will provide a platform for chemical screens to identify candidate small molecules. This project will utilise mutant rescue assays for screening that will take advantage of high throughput automated, quantitative drug screening (Sheffield Zebrafish Screening Unit). We have extensive experience of different drug screening assays using gene expression and fluorescence read outs with methods for high through-put screening with zebrafish.

Current therapeutics have limited proven efficacy in children with OI; understanding disease mechanism and identifying druggable targets for NBAS, a gene known to cause bone fragility will help treat NBAS-related phenotypes with potential wider utility.

The zebrafish is a uniquely powerful model for addressing important, clinically relevant questions in skeletal biology. In conjunction with patient-derived cells, we have compelling resources for delivery of this proposal. The combination of hypothesis-driven research, well-designed unbiased genetic screens, and potential for novel therapies will bring new advances to the field of bone disease and cell biology, and swiftly translate these into clinical improvements for my patients.

This project uniquely combines the clinical expertise and data of a leading OI clinician (primary supervisor) with existing tools and knowledge of zebrafish models generated in her laboratory. The synergy here will provide a basis for further projects in this critical area of science and bring about a step-change in OI treatment discovery for patients’ benefit.

Entry Requirements:

Candidates must have a first or upper second class honours degree or significant research experience. 

How to apply:

Please complete a University Postgraduate Research Application form available here: https://www.sheffield.ac.uk/postgraduate/phd/apply/applying.  Candidates will be required to complete a declaration form and upload it to their application.

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 – October 2024

For further information on this scheme please see – https://www.sheffield.ac.uk/postgraduate/phd/scholarships/faculty