Faculty of Medicine,Dentistry and Health Sciences Department of Pathology

Research Projects 2006 - Advanced Medical Science (AMS)

Project list

Confirmed

Previous Projects (may still be current)

Cord blood-derived adult stem cells.

Professor Bob Williamson and Dr Faten Zaibak
The Stem Cell Research Laboratory
Department of Pathology
Email: fzaibak@unimelb.edu.au

It has recently been shown that cord blood derived adult stem cells have the capacity to differentiate into cells from all three germ line layers (endoderm, ectoderm and mesoderm). This means they resemble embryonic stem cells, although “adult” in origin and completely ethical to work with. The objective of the stem cell research laboratory is to establish the scientific basis to make it possible to use these somatic stem cells for cell therapy to treat any diseased or injured tissue, and particularly to treat genetic diseases such as cystic fibrosis.

SAMPLE RESEARCH PROJECTS :

  1. Improving the propagation of cord blood derived stem cells and testing if they change in properties as they divide over several generations.
  2. Determining if cord blood stem cells can differentiate into lung cells in culture.
  3. Examining whether minor differences in protein sequence could lead to rejection of cord blood stem cells if used for cell therapy in cystic fibrosis.

TECHNIQUES:

 

Studying the activity of the amyloid precursor protein (APP) copper binding site.

Dr Roberto Cappai and Dr Giuseppe Ciccotosto
Department of Pathology
Email: r.cappai@unimelb.edu.au

Alzheimer's disease (AD) is a neurodegenerative disorder that attacks the elderly resulting in memory loss. The pathology of an AD brain shows abnormal protein deposits of amyloid plaques and widespread neuronal cell death. The amyloid deposits arise from the polymerization of a 4 kDa peptide (ABeta) which is derived from a precursor molecule called amyloid precursor protein (APP).

APP is part of a gene family which includes the amyloid precursor-like proteins 1 and 2 (APLP1 and APLP2). They all contain a single transmembrane domain, a large ectodomain and a short cytoplasmic tail. The extracellular domain contains binding sites for a range of ligands including heparin, proteases, lipoprotein receptors and copper. The N-terminal copper binding site (CuBD) is believed to be a regulator of Cu-homeostasis and can affect APP processing into ABeta. The hypothesis for this project is that the interaction of APP with copper influences cellular copper transport

This project will complement our current studies aimed at understanding APP structure and function. We have solved the structure of the N-terminal copper binding site and defined the residues involved in Cu-binding. We have also generated cell lines from APP, APLP2 and APP-APLP2 knockout mice.

AIM: To determine the role of the APP CuBD in Cu homeostasis using APP and APLP2 knockout cells.

APPROACH: This project will involve performing site-directed mutagenesis on the APP CuBD. These mutant APP genes will be transfected into APP and APLP2 knockout cells and the effect of the mutant APP on Cu transport and homeostasis will be measured. Furthermore, the effect of the mutations on APP processing into ABeta will also be studied.

EXPECTED OUTCOMES: We expect to determine how the Cu binding site modulates Cu homeostasis and the production of the ABeta peptide which underlies AD pathogenesis.

TECHNIQUES: This project will allow the student to learn a broad range of molecular biology techniques including cloning, PCR, mutagenesis and sequencing combined with cell culture and immunochemistry.

Correlation of molecular imaging and molecular pathology of cancer.

Assoc. Prof. Paul Waring, Dr. Rod Hicks, and Dr. Melanie Trivett,
Peter MacCallum Cancer Centre.
Email: Paul.Waring@petermac.org

This project aims to identify immunohistochemical markers that will help identify which cancers are suitable for positron emission tomography (PET) scanning. The project will correlate the results of diagnostic PET scanning with the expression of genes involved in the biochemical pathways detected by PET. You will perform a systematic review of over 3000 PET scan results from which you will identify a subset for further study. You will retrieve biopsy tissue from the study subset and perform immunohistochemistry to examine the tumour tissue for expression of various proteins. The project will expose you to diagnostic imaging (radiology), nuclear medicine (PET scanning), anatomical pathology and molecular biology. The data you generate and the tests you develop are likely to be incorporated into clinical practice.

Molecular pathology of familial cancer.

Assoc. Prof. Paul Waring and Assoc. Prof. Alexander Dobrovic,
Peter MacCallum Cancer Centre.
Email: Paul.Waring@petermac.org

This project aims to evaluate existing and develop new diagnostic molecular pathology tests that are to be used clinically to help identify individuals with an inherited predisposition to cancer. The project will involve the review of the results of existing test and the development of new diagnostic molecular techniques to be introduced into clinical practice. You will work in a diagnostic and research molecular pathology laboratory at Australia’s leading cancer center and will work closely with the Peter Mac Familial Cancer Clinic and leading cancer researchers. You will learn several molecular techniques (eg PCR, DNA sequencing) and develop a detailed understanding of cancer genetics and pathology. The data you generate and the tests you develop are likely to be incorporated into clinical practice.

Development of new molecular haematooncology tests.

Assoc. Prof. Paul Waring, Assoc. Prof. Alexander Dobrovic, Dr. David Westerman.
Peter MacCallum Cancer Centre.
Email: Paul.Waring@petermac.org

This project aims to evaluate existing and develop new diagnostic molecular haematooncology tests that are to be used clinically to help diagnose and monitor treatment responses in patients with lymphoma and leukaemia. The project will involve the review of the results of existing test and the development of new diagnostic molecular techniques to be introduced into clinical practice. You will work in a diagnostic and research molecular pathology laboratory at Australia’s leading cancer center and will work closely with haematooncologists and cancer researchers. You will learn several molecular techniques (eg PCR, DNA sequencing) and develop a detailed understanding of cancer genetics and haematopathology. The data you generate and the tests you develop are likely to be incorporated into clinical practice.

Predictive molecular markers for cancer treatment.

Assoc. Prof. Paul Waring, Assoc. Prof. Alexander Dobrovic, and Dr. Grant McArthur.
Peter MacCallum Cancer Centre.
Email: Paul.Waring@petermac.org

This project aims to identify and evaluate new diagnostic molecular tests that are to be used clinically to help identify tumours that are likely to be responsive to specific cancer treatments and to identify individuals who are likely to experience toxicity. The project will involve development of new diagnostic molecular techniques to be introduced into clinical practice. You will work in a diagnostic and research molecular pathology laboratory at Australia’s leading cancer center and will work closely with medical oncologists and leading cancer researchers. You will learn several molecular techniques (eg PCR, DNA sequencing) and develop a detailed understanding of cancer genetics, pathology and oncology. The data you generate and the tests you develop are likely to be incorporated into clinical practice.

Evaluation of pathology review for patients with cancer.

Assoc. Prof. Paul Waring, Dr. William Murray, Dr Hugh Turner, and Dr Stephen Lade.
Peter MacCallum Cancer Centre.
Email: Paul.Waring@petermac.org

This project aims to evaluate the clinical usefulness of reviewing the pathological diagnosis of cancer when patients are referred to a major cancer center for treatment. The anatomical pathologists at the Peter MacCallum Cancer Centre regularly review, at the request of the treating doctor, the original pathology material upon which the patient’s diagnosis was based. Not infrequently, the diagnosis or stage of the cancer is revised and the patient’s treatment altered. This project will systematically examine the last 2500 pathology reviews to determine the frequency of minor and major diagnostic discrepancies and will evaluate the clinical impact of major discrepancies on therapeutic decision-making. You will work in an anatomical pathology laboratory at Australia’s leading cancer center and will work closely with pathologists, medical oncologists, radiation oncologists, surgeons, cancer researchers and statisticians. You will develop a detailed understanding of cancer pathology, oncology and statistics. The data you generate is likely to be published and incorporated into clinical practice.

Molecular prediction of therapeutic response in cancer.

Alexander Dobrovic
Peter MacCallum Cancer Centre
Email: a.dobrovic@pmci.unimelb.edu.au

By and large, the increasing amount of molecular information potentially available doesn’t alter the clinical management of cancer patients. The exceptions, and there will be an increasing number of them, target therapies at specific genetic lesions e.g. Glivec, Herceptin. However, standard chemotherapy and radiotherapy remain viable options if we could predict responders and non-responders. We need to be able to stratify patients using molecular information to determine the susceptibility of their tumour to particular regimens. Our objective is to research the alterations of DNA repair in cancer patients. This will allow the identification of those pathways by which cancer cells with altered DNA repair genes can be targeted by specific therapies.

The cell has multiple repair pathways in order to survive the constant damage to the genome. Germline mutations in some repair genes are associated with autosomal recessive cancer predisposition syndromes, e.g. xeroderma pigmentosum. Other mutations in DNA repair manifest themselves as highly penetrant autosomal dominant cancer predisposition syndromes. Particularly striking is the association of hereditary non-polyposis colorectal cancer (HNPCC) with mutations in a number of genes, notably MLH1, MSH2 and MSH6, all in the mismatch repair pathway. Breast cancer is particularly associated with mutations in genes associated with the monitoring of double strand breaks i.e. BRCA1, BRCA2, ATM and CHK2.

Aims: To examine genes involved in the detection, response to and repair of DNA damage in common cancers in which DNA repair pathways have been implicated in the pathogenesis.

The project will involve one or more of the following;

  1. Identifying DNA repair genes that are hypermethylated in cell lines.
  2. Analysis of the identified methylated genes in tumour samples.
  3. Correlation of methylation data with microarray data
  4. Correlating these findings with the patient’s response to chemotherapy and outcome

Methods: PCR, RT-PCR, microarray analysis, real time PCR, sequencing, data retrieval

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