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

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.
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