Prof Brian BIgger
Dr R Holley
Prof S Flitsch
Applications accepted all year round
Self-Funded PhD Students Only
About the Project
Mucopolysaccharidoses (MPS) are inherited metabolic disorders caused by the deficiency of specific lysosomal enzymes required for the catabolism of glycosaminoglycans (GAGs) where each MPS type lacks a specific enzyme resulting in the build-up of GAGs in all cells of the body. The GAGs stored are heparan sulphate (HS), dermatan sulphate (DS), chondroitin sulphate (CS) or keratan sulphate (KS) which are complex polysaccharides that are viscous in nature and are important components of the extracellular matrix of organs, joint fluid, and connective tissue. Their accumulation occurs in a variety of tissues and is dependent on the location of the affected substrates and their rate of turnover. MPSs that store DS, CS or KS, such as MPS I, II, IV, VI, VII and IX tend to exhibit bone and joint disease whereas MPSs that result in the storage of heparan sulphate, (MPS I, II, III and VII), exhibit a neurological phenotype. MPSs also exhibit peripheral organ disease and types that store multiple GAGs exhibit multisystem disease. MPS affects children in the resulting in severe progressive neuronal decline, massive neuroinflammation characterised by microgliosis, visceral organ enlargement and dysfunction leading to death in early childhood. GAG accumulation and neuroinflammation appear to be linked processes. The child appears normal at birth and develops within the range of normal for the first year or two, but due to the accumulation of storage material, symptoms begin to appear.
During this PhD the aim will be to firstly determine the early role of GAGs in different MPS diseases using mouse models in house, establish the respective origin of inflammatory cells in disease and develop a specifically targeted stem cell gene therapy approach to treat the disease.
Research Techniques and skills
The candidate will learn a variety of cell culture techniques including primary mixed glial culture, 3D scaffolds, histology, molecular cloning, gene therapy and stem cell therapy skills. Glycobiology skills including AMAC, and immunohistochemistry. In vivo skills include intracranial surgical stereotaxy. This will be provided by senior laboratory members who have specific expertise in the areas above.
Candidates are expected to hold (or be about to obtain) a minimum upper second class honours degree (or equivalent) in gene therapy, biochemistry, glycobiology, stem cell biology or a related topic. Candidates with experience in gene therapy or glycobiology are encouraged to apply.
This project has a Band 3 fee. Details of our different fee bands can be found on our website (https://www.bmh.manchester.ac.uk/study/research/fees/). For information on how to apply for this project, please visit the Faculty of Biology, Medicine and Health Doctoral Academy website (https://www.bmh.manchester.ac.uk/study/research/apply/).
Informal enquiries may be made directly to the primary supervisor.
Bigger 2014 Discovery medicine 17 (94) 207-215 Novel Approaches and Mechanisms in
Hematopoietic Stem Cell Gene Therapy –review.
Wilkinson 2012 PlosOne 7 (4) e35787 Neuropathology in Mouse Models of Mucopolysaccharidosis Type I, IIIA and IIIB
Sergijenko 2013 Molecular Therapy 21 (10) 1938-49 Myeloid/Microglial driven autologous hematopoietic stem cell gene therapy corrects a neuronopathic lysosomal disease.