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Small molecule probes to study human enzymes involved in muscular dystrophy


Project Description

Background:
Proteins on the surface of cells are often modified with diverse, complex carbohydrate structures. These carbohydrates, named glycans, play central roles in biology by regulating, for instance, cell recognition and signalling events. At the same time glycans can form the basis of human disease, for instance when glycan interactions are hijacked by pathogens to enter host cells or when the lack of certain interactions leads to tumor metastasis. This project is centered around a specific type of glycan - named O-mannosyl glycan - that is unique to mammals and provides a vital link between neuromuscular cells and components of the extracellular matrix. Loss of these cell-matrix interactions, caused by problems with the correct assembly of the O-mannosyl glycan, causes a range of congenital muscular dystrophies. Although most of the enzymes involved in biosynthesis of the glycan have been identified, and they are known to cause muscular dystrophy when they lose their proper function, many of them remain poorly characterised. It is therefore unclear what the effect of specific genetic mutations is on the functioning of the corresponding enzymes and how this leads to specific disease phenotypes. In this project, we aim to generate small molecule probes targeting some of these disease-associated enzymes. These chemical tools will help us better understand the roles of the enzymes in disease pathology.

Objectives:
The aim of this study is to synthesise new small molecule probes that we can use to enhance our understanding of some of the key enzymes responsible for biosynthesis of O-mannosyl glycans. These tools will facilitate characterisation of enzyme function in vitro and in a cellular context, as well as characterisation of the resulting glycan structures on the cell surface. This information will not only provide novel insights into the pathway of O-mannosylation in mammalian cells but will also help address some of the gaps in our knowledge regarding the molecular and cellular consequences of genetic mutations that are known to cause muscular dystrophy.

Experimental approach:
In order to reach these goals, we will use an interdisciplinary approach that combines organic synthesis with biochemistry and cell biology. The project will involve:
1) synthesis of carbohydrate analogues that mimic the enzymes’ natural substrates but are modified in such a way that they enable us to study the enzyme’s activity;
2) development of in vitro enzyme assays to test the effectiveness of the new molecules;
3) use of the generated compounds to study enzyme function in vitro and in cell culture. Novelty
The project will generate novel chemical tools that we can use to study a pathway of protein glycosylation which is relatively poorly understood and for which such tools are currently not available. The new tools will therefore be of great value in elucidating the activity and roles of our target enzymes. The results will also have significant potential to drive further cutting-edge research into the functioning of the O-mannosylation pathway, both during normal cellular functioning and in the context of muscular dystrophy. This work will likely impact not only fundamental research, but also clinical research by helping us better understand how specific mutations in our target enzymes contribute to disease.

Training:
The training program will be of a cross-disciplinary nature, providing training in organic chemistry, biochemistry and a basic understanding of cell biology. Specific techniques include synthetic/carbohydrate chemistry, HPLC purification, LC-MS and NMR characterization, mammalian cell culture, SDS-PAGE, immunoblotting, and affinity purification. Attendance at group meetings joint with the Fascione and Parkin labs, and participation in departmental and YSBL seminars as well as relevant conferences, will further strengthen the training of the student in their multidisciplinary approach to their research.

All Chemistry research students have access to our innovative Doctoral Training in Chemistry (iDTC): cohort-based training to support the development of scientific, transferable and employability skills: https://www.york.ac.uk/chemistry/postgraduate/idtc/

Equality and Diversity
The Department of Chemistry holds an Athena SWAN Gold Award and is committed to supporting equality and diversity for all staff and students. The Department strives to provide a working environment which allows all staff and students to contribute fully, to flourish, and to excel: https://www.york.ac.uk/chemistry/ed/. This PhD project is available to study full-time or part-time (50%).

This PhD will formally start on 1 October 2020. Induction activities will start on 28 September.

Funding Notes

The studentship is fully funded for 3 years by a Department of Chemistry Teaching Studentship and covers: (i) a tax-free annual stipend at the standard Research Council rate (£15,009 for 2019-20), (ii) tuition fees at the UK/EU rate, (iii) funding for consumables. You need to submit a separate Teaching Studentship application: View Website

The sudentships is available to any student who is eligible to pay tuition fees at the home rate: View Website

References

Candidate selection process:
• Applicants should submit a PhD in Chemistry application to the University of York by 8 January 2020
• Supervisors may contact candidates either by email, telephone, web-chat or in person
• Supervisors can nominate up to 2 candidates to be interviewed for the project
• Candidates will be invited to a panel interview at the University of York in the week commencing 10 February 2020
• The awarding committee will award studentships following the panel interviews
• Candidates will be notified of the outcome of the panel’s decision by email

How good is research at University of York in Chemistry?

FTE Category A staff submitted: 47.06

Research output data provided by the Research Excellence Framework (REF)

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