Honours Project Book - Faculty of Health Sciences - University of ...

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Matrix Biology Unit Location: Women’s and Children’s Hospital Supervisor/Contact Persons Dr Sharon Byers Phone: 8161 7093 sharon.byers@adelaide.edu.au Dr Ainslie Derrick-Roberts Phone: 8161 6373 ainslie.derrickroberts@adelaide.edu.au Our research interest lies in the regulation of a group of complex carbohydrates called glycosaminoglycans (gags). Gags are found in all tissues where they define tissue structure and modify tissue growth through the regulation of growth factor activity. They are constantly synthesised and degraded as part of normal development. Defects in degradation lead to the mucopolysaccharidosis (MPS) group of inherited metabolic disorders. Our laboratory is focused on the characterisation of disease progression and the development of safe and effective therapies for MPS children and played a key role in the commercialization of enzyme replacement therapy. The laboratory is situated in the department of Genetics and Molecular Pathology, SA Pathology (WCH site). The department is the Australasian centre for the diagnosis and treatment of children with MPS. The multiple organs systems affected by the accumulation of undegraded gag in MPS presents a challenge to the clinical management of affected children. While somatic tissues such as liver and kidney are amenable to replacement therapies, the brain and the cartilage component of the musculoskeletal system are untreatable. Students will join ongoing projects in one of the following areas:- Key Words: genetic disease, childhood disorders, therapy, murine models of disease, behavioural tests, bone growth PROJECT: (Basic) Targeting CNS pathology in MPS disorders. Project Background CNS pathology that manifests as a severe, progressive loss of cognitive function is a major symptom of 7 of the 11 MPS types and is currently untreatable. The aim of this project is to find a minimally invasive approach to treat CNS pathology in MPS disorders. Gene therapy replacement of the missing gene has shown promising results in mouse models (Anson et al., 2011), however has a limited effect on the CNS due to the presence of the bloodbrain barrier. The aim of this project is to improve blood brain barrier transport using a modified enzyme to enhance receptor mediated transport across the blood-brain barrier. By combining gene therapy to increase residual enzyme levels with small molecule SDT (Derrick-Roberts et al., 2012) to decrease gag levels is another approach to improve the outcome of CNS disease in MPS disease also under investigation. Students undertaking this project will learn fundamental research techniques applicable to a wide range of research areas. These include small animal handling, behavioural testing (eg water maze tests), enzyme assay, electrophoresis and carbohydrate biochemistry. Equipment to be used will include: microscopes, centrifuges, electrophoresis equipment, fluorimeter, mass spectrometer and laminar flow/biohazard hoods. References Roberts ALK, Rees MH, Klebe S, Fletcher JM and Byers S. (2007): Improvement in behaviour after substrate deprivation therapy with rhodamine B in a mouse model of MPS IIIA. Molecular Genetics and Metabolism, 92: 115-121. Anson DS, McIntyre C, Byers S. (2011): Therapies for neurological disease in the mucopolysaccharidoses. Curr Gene Ther. 11: 132-43. Derrick-Roberts ALK, Ly M, Marais W and Byers S. (2012). Rhodamine B and 2-acetamido-1,3,6-tri-Oacetyl-4-deoxy-4-fluoro-D-glucopyranose (F-GlcNAc) inhibit chondroitin/dermatan and keratan sulphate synthesis by different mechanisms in bovine chondrocytes. Mol. Genet. Metab. 106: 214-20. PROJECT: (Basic) Understanding skeletal disease in MPS patients. Project Background Direct injection of enzyme into the joint space increases the localized concentration of enzyme replacement therapy (ERT) and improves joint outcome (Auclair et al 2006, 2007). We have recently shown that the same improvement can be achieved 57 |
y a gene therapy approach to transduce joint cells (Byers et al 2009). In this project students will join an ongoing project to investigate the efficacy of systemic gene therapy alone or in combination with intra-articular gene therapy to prevent the development of both bone and joint pathology. Short stature is a feature of 6 of the 11 MPS disorders which leads to problems with mobility. Therapy options are limited and ERT available for some MPS disorders does not increase bone length in affected children even though it has a positive effect on other symptoms. This suggests that we need a better understanding bone growth and by isolating distinct regions of the growth plate responsible for bone lengthening we can identify key markers involved in long bone growth which can be new targets to improve short stature. Students undertaking this project will learn fundamental research techniques applicable to a wide range of research areas. These include small animal handling, bone histomorphometric techniques, micro CT, laser capture microdissection, real-time PCR, electrophoresis and carbohydrate biochemistry. Equipment to be used will include: microscopes, image analysis equipment, centrifuges, electrophoresis equipment, fluorimeter and laminar flow/biohazard hoods. References Macsai CE, Derrick-Roberts AL, et al. (2012): Skeletal response to lentiviral mediated gene therapy in a mouse model of MPS VII. Mol Genet Metab. 2012 Jun;106: 202-13 Byers S, Rothe M, et al. (2009). Lentiviral mediated correction of MPS VI cells and gene transfer to skeletal tissues. Molecular Genetics and Metabolism, 97: 102-108. Auclair D, Hein LK, et al. (2006): Intra-articular enzyme administration for joint disease in feline mucopolysaccharidosis VI: Enzyme dose and interval. Pediatric Research, 59: 538-542. Auclair D, Hopwood JJ, et al. (2007): Intra-articular enzyme administration for joint disease in feline mucopolysaccharidosis VI: Long-term therapy. Molecular Genetics and Metabolism, 91: 352-61. 58 |
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SCHOOL OF PAEDIATRICS AND REPRODUCT
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Make a difference "The recent Excel
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Honours graduate career pathways Ou
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Page 10 and 11: Discipline of Obstetrics and Gynaec
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Page 18 and 19: products, but also naturally occurr
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Page 22 and 23: PROJECT: (Basic) Stem Cells of Ovar
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Page 28 and 29: persist long term. There is new evi
Page 30 and 31: PROJECT: (Basic) Behavioural effect
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Page 40 and 41: Reproductive Biotechnology Group Su
Page 42 and 43: that versican is pivotal in promoti
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Page 48 and 49: PROJECT: (Basic) Viral Recognition
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Page 52 and 53: PROJECT: (Basic) Measurement of vit
Page 54 and 55: Craniofacial Research Group Contact
Page 56 and 57: Lysosomal Biology, Lysosomal Diseas
Page 60 and 61: Molecular Immunology Cheryl Brown P
Page 62 and 63: Fig 4. Lentiviral delivery of shRNA
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Page 66 and 67: Paediatrics and Child Health, Flind
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Page 72: Index Breast Biology and Cancer, 16
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