External Honours Projects

The Department of Physiology on occasion accepts into its Honours Course students who are performing their research in laboratories outside the Department. The project must be closely allied to physiology and an internal supervisor who is familiar with the area must be prepared to act as the associate supervisor. The student should normally have undertaken at least one 3rd year course in Physiology and must attend the teaching sessions for Honours students which occur weekly within the Department.

Supervisors and laboratories which have indicated their interest in taking such students include

ANZAC Research Institute

The ANZAC Research Institute is a new purpose built research facility in the grounds of Concord Hospital, Concord. The Bone Biology Laboratory is a well equipped research facility. The research group includes three scientists with research assistants and students and is conducting research into bone metastasis and osteoporosis,

Project 1.

Breast Cancer Metastasis
This projects investigates the factors which drive the propensity of breast cancer cells to establish secondary tumours in bone. The student will use fluorescently labelled cells to track the targeting of human breast cancer cells to bone in mice. The bone metabolism in the mice will be altered using pharmacologic agents to determine if this changes breast cancer cell trafficking. This project will involve small animal handling, cell culture, histology and molecular biology.

Project 2.

Glucocorticoid regulation of osteoblasts
Primary cultures of osteoblasts will be derived from wild type and transgenic mice that have osteoblast specific inhibition of glucocorticoid (cortisol) signalling that results in altered ability to form bone. This project will use detailed cell based gene expression studies to determine the pathways impacted by blocking of glucocorticoid signalling. Techniques developed will be cell culture, molecular biology, and small animal handling.

For more information contact:

Dr Colin Dunstan
Principal Research Fellow
ANZAC Research Institute
(in the grounds of Concord Hospital, Concord)
+61 2 9767 9163
cdunstan@med.usyd.edu.au

VASCULAR BIOLOGY RESEARCH CENTRE
DEPT SURGERY, WESTMEAD HOSPITAL

We are at the cutting edge of vascular research, recently identifying the presence and role of progenitor cells in the development of atherosclerosis. Our success comes from the direct interaction between surgeons and scientists; enabling our research to span from a basic fundamental level to a clinical research angle. We have both honours and PhD projects available.

THE ROLE OF PROGENITOR CELLS IN DISEASE

Our aim is to understand the role of progenitor cells in wound healing so that we can alter its progression to give a better outcome in various disease states. We are focusing in particular on atherosclerosis (heart disease) and the wound healing response (intimal hyperplasia) generated upon its treatment. Our work has attracted interest from other researchers and as such we have established collaborations with several other groups.

Our current research projects (which will continue next year) include:
1.    The role of progenitor cells in atherosclerosis (vascular disease)
We have recently identified the presence and role of a progenitor cell in atherosclerosis. We are currently comparing samples from patients versus controls to determine what factors effect differentiation of progenitor cells in atherosclerosis development.

2.    The pluripotent nature of progenitor cells in wound healing
Wound healing involves a range of cells interacting to restore tissue integrity. We are determining what range of cells the progenitor can differentiate into in this process.

3.    The role of platelets in progenitor cell differentiation
Our preliminary work has shown that platelets can effect the differentiation of the progenitor cells into different cell types depending on how they are allowed to interact. We are examining what factors from the platelets effect this.

Contact:
Dr Heather Medbury
Phone: 9845 7677
Email: heather_medbury@wsahs.nsw.gov.au
www.wmi.usyd.edu.au/reseacentres/surgery.html

Brain and Mind Research Institute

Honors projects (9 months): Pathogenesis of Alzheimer’s disease

Available tools and techniques:

· Transgenic mouse models, transgenic brain bank, tissue culture lines

· Molecular biology (DNA, RNA work)

· Cell biology, histology

· Animal handling (stereotaxic injections, production of transgenic mice, micromanipulation)

· Proteomics, transcriptomics

· Biochemistry (to some extent)

Possible project outlines:

Histological and functional validation of candidate proteins identified in models of Alzheimer’s disease by Functional Genomics

Using proteomics, we have identified differential protein spots in a mouse model of Alzheimer’s disease (AD). The aim of the project is to use antibodies to determine by immunohistochemistry and Western blot analysis which of the candidates is differentially regulated in human AD and control brains. Where applicable, functional assays will be performed (for example phosphorylation assays for kinases or depolarisation assays for mitochondrial proteins. Part of these assays may be done in our tissue culture systems).

Transport of Aβ in the mouse brain

The amyloid cascade hypothesis claims that Aβ induces the tau pathology in AD and by that, in part, exerts its toxicity. When added extracellularly, Aβ may exert its toxic effects by pore formation, uptake and transport, via contribution of the glial compartment, and by damage of nerve terminals. We propose to stereotaxically inject fibrillar preparations of either fluorescently or 3H-labelled Aβ42 into the CA1 region of the hippocampus and to determine whether Aβ42 is transported in vivo along projections from the amygdala to the CA1 region.

Specificity of the Aβ42-mediated induction of tau tangles (NFTs) in vivo

Tau tangle (NFT) formation characterizes many neurodegenerative disorders besides AD. Whereas in some diseases, they are the only type of proteinaceous aggregate, in others they co-occur with fibrillar aggregates such as Aβ in AD, the scrapie form of the prion protein (PrPsc) in prion disorders, or the amyloid-Bri (A-Bri) peptide in British dementia. Thus, with respect to tau-related pathogenesis, this project addresses the question whether the observed increase in NFT numbers in P301L mice caused by stereotaxic injection of fibrillar preparations of Aβ42 could be induced by other fibrillar aggregates such as PrPsc, A-Bri, or the amylin which is aggregating in diabetes.

Role of oxidative stress in transgenic mice with an Alzheimer-like tau pathology

A proteomic and functional analysis of P301L tau transgenic mice (our major Alzheimer model) revealed a mitochondrial dysfunction. The aim of this project is to expose age-matched hemizygous and homozygous P301L mice to oxidative stress, determine functional impairment and correlate these with the tau pathology in distinct brain areas using Western blotting and immuno-histochemistry

Dissection of the functional domains of tau by a transgenic approach

The tau protein is organized into functional domains termed projection domain, proline-rich region, repeat region and carboxy-terminal tail, with the latter possibly inhibiting tau aggregation. Some of the interaction partners of these domains have been identified. As tau pathology represents a common end point of several diseases collectively termed tauopathies it will be important to understand the role of the complex interactions of tau in vivo. The project involves the design of novel transgenic animal models where individual interactions are disturbed. In addition, specific amino acid substitutes will be introduced assisting in the analysis.

Transgenic mouse model with a brain pathology in the skin

The brain is difficult to access for experimental manipulation. The mainly neuronal protein tau aggregates in human disorders. Tau is also expressed at lower levels in the skin, and many signalling pathways with tau as a target are shared between the brain and the skin. To circumvent the limitations of the brain’s inaccessibility, we generated transgenic mice which express mutant tau in the skin. This project involves a histopathological and Western blot analysis of this mouse strain, combined with depilation to determine the hair cycle-dependent pathology.