Sugars and their derivatives (Glycoproteins and glycolipids) play multiple roles in health and disease and are interesting targets for therapeutic intervention involving chemical biology and medicinal chemistry programs. Anomalous sugar metabolism is the cause of major diseases that affect numerous organs including brain and muscles. Sialic acid plays a major role in several biological processes ranging from immunity, cell adhesion, neurobiology and deficiency or overexpression of sialic acid, is the causes of many diseases including: Salla disease, mucolipidosis type I (sialidoses) and GNE myopathy (GNEM), a condition that leads to weakness and wasting of muscles in legs and arms and the focus of this project. Although this genetic disease is characterized with degeneration of muscle cells, it is also shown to have other hallmarks such as aggregation of Amyloid β and accumulation of phosphorylated tau and other misfolded proteins in muscle cells similar to Alzheimer disease in the brain.
On this project the student will synthesise mannosamine and mannosamine phosphate derivatives that will then be used to investigate possible defects in the sialic acid biosynthesis in GNEM and as a potential therapeutic agent for this disease. This is an International and multidisciplinary project, and the student will have an opportunity to join a research group that is part of the European Joint Program on Rare Disease (EJPRD) consortium which includes glycobiologist with expertise in CDGs in Portugal and Germany and expert in glycomics and metabolomics in Italy. There will be the opportunity to spend some time in their laboratories to gain skills in sialic acid biology and metabolism.
A general outline and timeline of work is described below:
Year 1: Training in synthetic organic chemistry and analysis of complex organic molecules (carbohydrates and their fluorinated analogues) via multinuclear 1D & 2D NMR spectroscopy. Training in HPCL and LC-MS analysis of organic samples and monitoring enzymatic reactions via 19F and 31P NMR spectroscopy as well as LC-MS. Determination of sialic acid in GNE cells via established protocols.
Year 2: Synthesis of fluorescent carbohydrate derivatives and their biological evaluation in rescuing the GNE defects in patient-derived cellular models.
Year 3: Improvement of the molecules produced in year 2 and their further evaluation in other glycosylation disorders.
The Cardiff School of Pharmacy and Pharmaceutical Sciences is the number one School across England and Wales, and the second highest across the whole of the UK (The Complete University Guide 2020). Research at Cardiff is working across disciplines to tackle major challenges facing society, the economy, and the environment. Cardiff School of Pharmacy and Pharmaceutical Sciences has very well-equipped laboratories with 500 MHz NMR, LC-MS and modern cell biology facilities with associated expertise in biological validation of new drugs targeting numerous diseases.
Training and Development Opportunities
Training will be provided in synthetic organic chemistry with particular focus in organophosphorus and organofluorine compounds. optical spectroscopy and microscopy, sample preparation, knowledge of the field. Transferable skills in presentation, data handling and analysis, programming, scientific writing. Global mobility opportunities - visiting partner groups across Europe and beyond. Academic career skills – the student will be able to participate in teaching and demonstrating, and scientific publishing. By working on this project, the student will acquire detailed knowledge of synthetic chemistry, drug design, imaging tools, cell culture, design of biological assays, data analysis interpretation and problem solving. The student will also have the opportunity to present his/her research in our weekly lab meetings and to the consortium bimonthly meetings. A highly motivated and dedicated student will gain a thorough training in synthetic organic chemistry and biochemical diagnostic tools and be rewarded with a highly stimulating project that will shape the future of this exciting new research program.
Potential students should hold a good UK bachelor’s degree (first or upper second-class honours degree) or a MSc degree in chemistry or a related subject. Applications are particularly welcome from students with experience in organic synthesis and HPLC and/or LC-MS analysis
Formal enquiry can be directed to Dr. Pertusati at email@example.com
How to Apply
Applicants should apply to the Doctor of Philosophy (Pharmacy) with a start date of January 2022, by visiting our website.
In the research proposal section of your application, please specify the project title and supervisors of this project and copy the project description in the text box provided. In the funding section, please select 'I will be applying for a scholarship/grant' and specify that you are applying for advertised funding from Targeting Sialic Acid biosynthetic pathway for potential GNE Myopathy therapeutics.
- an upload of your CV
- a personal statement/covering letter
- two references
- current academic transcripts/certificates.
Applicants whose first language is not English will be required to demonstrate proficiency in the English language (IELTS 6.5 with a minimum subscore of 5.5 or equivalent).