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

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Lysosomal Biology, Lysosomal Diseases Research Unit Supervisor/Contact Person Dr Maria Fuller Phone: 8161 6741 maria.fuller@adelaide.edu.au Location: SA Pathology, Women’s and Children’s Hospital The Lysosomal Diseases Research Unit is highly regarded by its peers internationally for its seminal scientific contributions to the area of lysosomal research. Its research has resulted in FDA approval of first-ever treatments for two lysosomal storage disorders. The Unit consists of about 35 research staff and students working on a range of projects directed at understanding, improving diagnostic capabilities and treatment for a group of inherited metabolic diseases, known as lysosomal storage disorders. The Lysosomal Biology section of the Unit is currently investigating the role of the lysosome with respect to lipid metabolism in conditions outside the spectrum of classical lysosomal storage disorders, such as diabetes, metabolic syndrome, obesity, and Alzheimer’s and Parkinson’s diseases. We utilise state-of-the-art technology, including electrospray ionisation-tandem mass spectrometry, and lipid analytical techniques developed in our group. This technology provides a powerful platform to the investigation of metabolic disease. In February this year the group acquired a Waters Synapt High Definition mass spectrometer – the first one of its kind in Australia – capable of metabolomics, proteomics and MALDI imaging. This instrument is unique in offering an additional dimension to the analysis of compounds by using ion mobility separation, which allows compounds to be differentiated by size and shape. The following projects will give students broad scientific skill in cell models of disease, cell biology and the latest mass spectrometry technology in a highly challenging and stimulating academic environment. The student will also have ample support from other staff within the group who are experts in the methodology used (pictured above). Students will have the opportunity to participate in regular scientific discussions and meetings within the Unit. PROJECT: (Basic) Lipid disturbances in Neimann Pick C disease. Project Background Niemann-Pick C (NPC) disease is a hereditary cholesterol storage disorder resulting in severe neurovisceral pathology for which there is no cure. Many of the known risk factors of other diseases such as Alzheimer’s disease are also associated with cholesterol metabolism. This project proposes a “lipidomics” approach to identify the type of lipid alterations that occur secondarily to impaired cholesterol homeostasis using NPC patient cultured skin fibroblasts as a cell model. Sub-cellular fractionation techniques will also be employed to determine the location of these lipid alterations within the cell. The second part of this project will evaluate the possibility of normalising these lipid alterations by supplementing the culture media with particular fatty acids and drugs of lipid metabolism, as a potential therapeutic strategy for diseases of cholesterol metabolism. The overall scientific objective of this project is to identify lipid alterations that may be treated with diet and/or conventional drugs, providing a treatment for many individuals with diseases of cholesterol metabolism, including Alzheimer’s and NPC. The student will gain experience in cell culture and a variety of cell biology techniques including sub- cellular fractionation, as well as learning aspects of mass spectrometry. PROJECT: (Basic) Sphingolipids in diabetes and Gaucher disease. Project Background The membranes of mammalian cells are composed of an ordered array of lipids, and in many instances chemical or functional changes in these membranes are central to the pathogenesis of disease. We have shown that membrane lipids are altered in lysosomal storage disorders, and recent studies in the glycosphingolipid storage disorder, Gaucher disease, associate such lipid alterations with insulin resistance. It is now obvious that lysosomal storage disorders and insulin resistance diabetes share disturbances in sphingolipid metabolism, and because sphingolipids predominate in membrane rafts, the mechanistic link may be mediated by rafts. Rafts are specialised membrane microdomains that facilitate interactions between the protein and lipid components of signalling pathways. This project proposes to determine the lipid composition of membrane rafts in cell models of Gaucher disease and insulin resistant diabetes to unravel common nodes of interactions between these two pathogenic mechanisms. For effective long term-treatment of these conditions, understanding the pathogenic mechanisms will be imperative. 55 |
The student will gain broad experience in cell culture with both primary and gene knockdown immortalised cell lines. The student will gain experience in Western blot analysis, membrane microdomain isolation and various aspects of mass spectrometry. Publications Hein LK, Meikle PJ, Hopwood JJ, Fuller M. (2007) Secondary sphingolipid accumulation in a cell model of Gaucher disease. Mol Genet Metab 92, 336-45. Meikle PJ, Whitfield PD, Rozaklis T, Blacklock D, Duplock S, Elstein D, Zimran A, Mengel E, Cannell P, Hopwood JJ, Fuller M. (2008) Plasma lipids are altered in Gaucher disease: Biochemical markers to evaluate therapeutic intervention. Blood Cells Mol Dis 40, 420- 7. Meikle PJ, Duplock S, Blacklock D, Whitfield PD, Macintosh GL, Hopwood JJ, Fuller M. (2008) Effect of lysosomal storage on bis(monoacylglycero) phosphate. Biochem J 411, 71-8. Fuller M, Rozaklis T, Lovejoy M, Zarrinkalam K, Hopwood JJ, Meikle PJ. (2008) Glucosylceramide accumulation is not confined to the lysosome in fibroblasts from patients with Gaucher disease. Mol Genet Metab 93, 437-43. Hein LK, Duplock S, Hopwood JJ, Fuller M. (2008) Lipid composition of microdomains is altered in a cell model of Gaucher disease. J Lipid Res 49, 1725-34. 56 |
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SCHOOL OF PAEDIATRICS AND REPRODUCT
Page 4 and 5:
Make a difference "The recent Excel
Page 6 and 7: Honours graduate career pathways Ou
Page 8 and 9: Honours Scholarships and Support Sc
Page 10 and 11: Discipline of Obstetrics and Gynaec
Page 12 and 13: Discipline of Obstetrics and Gynaec
Page 14 and 15: Clinical Studies and Trials The Obe
Page 16 and 17: Cerebral Palsy Research Group The C
Page 18 and 19: products, but also naturally occurr
Page 20 and 21: disruption of either Clock or Bmal1
Page 22 and 23: PROJECT: (Basic) Stem Cells of Ovar
Page 24 and 25: Early Development Group Contact Per
Page 26 and 27: Early Life Programming of Health an
Page 28 and 29: persist long term. There is new evi
Page 30 and 31: PROJECT: (Basic) Behavioural effect
Page 32 and 33: Gamete and Embryo Biology Laborator
Page 34 and 35: improve developmental potential in
Page 36 and 37: PROJECT: (Basic) Factors that regul
Page 38 and 39: Pregnancy and Development Group Con
Page 40 and 41: Reproductive Biotechnology Group Su
Page 42 and 43: that versican is pivotal in promoti
Page 44 and 45: Reproductive Endocrinology Group Su
Page 46 and 47: Treg fate-determining transcription
Page 48 and 49: PROJECT: (Basic) Viral Recognition
Page 50 and 51: Child Nutrition Research Centre (CN
Page 52 and 53: PROJECT: (Basic) Measurement of vit
Page 54 and 55: Craniofacial Research Group Contact
Page 58 and 59: Matrix Biology Unit Location: Women
Page 60 and 61: Molecular Immunology Cheryl Brown P
Page 62 and 63: Fig 4. Lentiviral delivery of shRNA
Page 64 and 65: the two most common human polyA exp
Page 66 and 67: Paediatrics and Child Health, Flind
Page 68 and 69: Vaccine Safety Research Group Super
Page 70 and 71: introduction of the rotavirus vacci
Page 72: Index Breast Biology and Cancer, 16
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