Rare diseases affect over 3.5 million people in the UK and recent medical advances have provided the means to generate potential treatments for several rare diseases that have been studied to-date but have no treatment. Importantly, a large proportion (80%) of these diseases are caused by specific alterations (mistakes) in the genetic building blocks or DNA of affected patients. New scientific methodologies, such as gene therapy, have been developed which could enable us to replace or repair DNA mistakes, but such treatments are extremely expensive. Gene therapies also take time to develop and may not be an option for all rare disease patients. Hence, there is a need for having a multi-pronged approach including drug repurposing to find novel therapies for rare neurodevelopmental disorders (RNDDs). The focus of this proposal is drug repurposing for HNRNPU.

Heterogeneous nuclear ribonucleoprotein U (HNRNPU) syndrome is one such RNDD which leads to developmental delay and seizures. We will harness significant local expertise including ongoing work on developing AAV-9 gene therapy for HNRNPU-related disorder in this proposal. The underlying problem is that patients produce insufficient HNRNPU protein. Our overall goal is to develop new treatments to make this condition better. Specifically in this project, we will test the approach of drug repurposing using patient cellular models of HNRNPU syndrome to identify candidate drugs, to check if we are able to restore normal cellular functions. This is an essential first step in the pathway towards developing new treatments for HNRNPU syndrome.

Current modalities of treatment include supportive care for the developmental delay and attaining seizure control through use of multiple medications. This may or may not achieve good seizure control and hence, there is a real and urgent need to do better. HNRNPs including HNRNPU are linked to various diseases and knowledge gained from this proposal will be more widely applicable to all RNDDs.

Entry Requirements:

Candidates must have a first or upper second class honours degree or significant research experience. A real motivation and passion to transform the care and treatment provided for patients with rare diseases is an essential criterion for this application. In addition, candidates must be self-motivated, have the ability to think independently, use own initiative, have good communications skills and be well-organised including good time management. An MSc or experience in bioinformation, molecular genetics, including data mining, cell culture and in vivo studies would be desirable but not essential.

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.

Enquiries:

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

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

Whole Genome Sequencing (WGS) is a new genomic testing technology and process which became available through the NHS in April 2022. The process of WGS is multifaceted and facilitated across multiple clinical departments within the NHS. The National genomic Research Library (NGRL) is a comprehensive database that enables approved researchers to access de-identified genomic data, health data and samples. It is a partnership between NHS England and NHS Improvement (NHSE/I) and Genomics England. This central resource, linked to the Genomic Medicine Services (GMS), aims to provide access to research opportunities to improve diagnoses and our understanding of health and disease, as well as accelerate the development of new biomarkers, diagnostics and therapeutic agents. This proposal will involve mining data within the NGRL to identify novel causes of rare disease including neurodevelopmental disorders.

Objectives:

1.     Access data from within NGRL looking at specific disease phenotypes

2.     Identify potential causal genes and correlate with international datasets

3.     Functional work to understand mechanism of action

4.     Cohort papers based on novel gene discovery

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 bioinformation, molecular genetics, including data mining, 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: www.shef.ac.uk/postgraduate/research/apply

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