Research outline - Molecular Neuropathology Laboratory

Within: Bosch Institute, Discipline of Pathology

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Overview of research program

Epigenetics of human gliomas

This project is examining DNA changes associated with gene silencing (DNA methylation) in specific chromosomal regions of human brain tumours (oligodendrogliomas). Using DNA microarray technology we have produced a comprehensive ‘map’ of the regions commonly affected in oligodendrogliomas, identifying genes which have been consistently silenced, and hence are likely important in tumour formation.

Histopathology of oligodendroglioma
AB

Histology of normal brain white matter (A) and of a Grade II oligodendroglioma (B).
Oligodendrogliomas are diffuse infiltrative tumours characterised by cells morphologically resembling oligodendrocytes with a perinuclear halo (“fried egg” appearance).

Combined bisulphite restriction analysis (COBRA) for methylation

The methylation status of a gene in a tumour sample can be determined by restriction digest profiles.
Restriction endonucleases specific for methylated DNA sequences (bisulphite converted) are used to digest PCR amplicons from a tumour sample.
Positve (Pos) and negative (Neg) methylated controls (Meth Ctrl) and the molecular weight (MW) marker are indicated.


Prognostic molecular markers in gliomas

Co-deletions of the short arm of chromosome 1 (1p) and the long arm of chromosome 19 (19q) in gliomas is associated with prolonged survival time and better response to adjuvant therapy. We are investigating ways to simply and inexpensively assay these chromosomal deletions in brain tumours.
We are also actively searching for novel prognostic markers that may be helpful in guiding therapeutic decisions in glioma patients.

microscopy images

Fluorescence in situ hybridisation with probes that bind to each arm of chromosomes 1 and 19 can be used to visualise the loss of 1p and 19q in tumour cells.

Small non-coding RNAs in schizophrenia

Schizophrenia is a common and devastating disease with an inherited component, but which has so far eluded attempts to identify common molecular aberrations associated with its onset. We are interested in the possible contribution of disordered small regulatory RNAs in this disease. These non-coding RNAs are recently discovered classes of RNA molecules that act in complex networks to influence gene expression at both the DNA and RNA level. They are highly expressed in the brain and provide a mechanism to link environmental experiences with the genome.
Their role in numerous disease processes is only now being elucidated.

Royal Prince Alfred Hospital (RPAH) and University of Sydney brain tumour and tissue bank

Established in 2006, with the support of RPAH Departments of Neuropathology and Neurosurgery, the bank collects neurosurgical tissue not required for diagnostic purposes to store it for use in medical research. Banking of tissue requires full informed consent from patients and/or their families.
The bank has full ethics approval from the Ethics Review Committee (RPAH Zone) of the Sydney South West Area Health Service.

Major funding sources

  • NSW Cancer Institute, Clinical Research Fellowship
  • Pfizer Neurosciences Research Grant
  • St. Vincent's Clinic Foundation Research Grant

Selected publications

Bobryshev, Y., Tran, D., Killingsworth, M., Buckland, M., Lord, R. Dendritic Cell-Associated Immune Inflammation of Cardiac Mucosa: A Possible Factor in the Formation of Barrett's Esophagus. Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 2009; 13:442-50.

Gilbert, D., Buckland, M., Abi-Hanna, D. Education and imaging. Gastrointestinal: Upper gastrointestinal bleeding after radiation microspheres. Journal of gastroenterology and hepatology. 2009; 24:324.

Leecy, T., Buckland, M., Turner, J., Earls, P. The use of immunohistochemistry in the diagnosis of primary salivary duct carcinoma: three case reports. Pathology. 2008; p. 434-7.

Stankovic, R.K., Chung, R.S., Penkowa, M. Metallothioneins I and II: neuroprotective significance during CNS pathology. Int. J. Biochem. Cell. Biol. 2007; 39:484-9.

Newland, L., Walsh, A., Gilbert, D., Buckland, M. Selective internal radiation therapy: a case of SIR-Sphere associated duodenal ulceration. Pathology. 2007; p. 526-528.

Buckland, M., Leahy, B., Lukeis, R., Suter, M., Turner, J., Morey, A. Molecular testing for paraffin embedded material. Pathology. 2006; p. 602.

Stankovic, R.K., Li, Z. Decreased neurofilament density in large myelinated axons of metallothionein-I, II knockout mice. Neurosci. Lett. 2006; 402:1-6.

Liu X.F., Moon H., Buckland M., Cunningham A., Zhou M.-D., and Graham R. Genetic disruption of the neuregulin cytoplasmic tail leads to loss of function. Proceedings of the National Academy of Science, USA. 1999; 95(22); 13024-9.

Buckland, M. and Cunningham, A. M. Expression of the neurotrophic factors BDNF, CNTF and GDNF in the normal and regenerating olfactory system. 1999; NY Annals Sci. 30:855:260-5.

Buckland, M. and Cunningham, A.M. Changes in expression of BDNF, CNTF and GDNF in the regenerating olfactory neuroepithelium. Neuroscience. 1999; 90(1):333-47.

Major collaborations

  • A/Prof Reginald Lord, St Vincent's Centre for Applied Medical Research, Darlinghurst, Sydney
  • Professor David Martin, CHORI, California, USA ,
  • Professor Mahlon Johnston, URMC, Rochester New York, USA.