Comparative biochemistry researches the evolution of protein structure and function, evolution of thyroid hormone distribution, and non-standard animal models for investigating biochemical processes.
We are interested in many aspects of comparative biochemistry, including the evolution of protein structure and function, evolution of thyroid hormone distribution, and non-standard animal models for investigating biochemical processes.
Our work includes investigations using Australian and American marsupials, salt-water crocodiles, lampreys, elephant sharks and genetically modified mice.
We are currently using marsupial models for elucidating mechanisms of disease and repair in humans. The elephant shark is proving an interesting model for bone formation. We also use knockout mice to investigate the effects of the absence of a specific protein in neural stem cell cycles.
- Associate Professor Samantha Richardson
- Mr Damian D'Souza, PhD student
- Mr Bandar Alshehri, PhD student
- Mr Roshen Wijayagunaratne, volunteer
- J. Danks, RMIT University
- S. Petratos, Monash University
- N. Saunders and K. Dziegielewska, University of Melbourne
- A. Hill, University of Melbourne
- B. McAllan, University of Sydney
- B. Demeneix, Muséum National d’Histoire Naturelle, Paris
- V. Darras, K. U. Leuven, Belgium
- K. Altland, Giessen Universität, Germany
- K. Yamauchi, Shizuoka University, Japan
- V. Cody, Hauptman-Woodward Medical Research Institute, Buffalo NY
- Australian Academy of Science, Scientific Visits to Japan grant (2011)
- Australian Research Council. $225,000 (2010 – 2012)
- Victorian Neurotrauma Initiative. $1.2M (2007 – 2010)
1. Mechanisms of transthyretin (TTR) amyloid formation
Transthyretin (TTR) is a protein important in the delivery of thyroid hormones via the blood and the cerebrospinal fluid. For unknown reasons, TTR can also form insoluble fibrils (amyloid) which deposit on cell membranes and disrupt normal cellular function. At least 25% of people over the age of 75 have TTR amyloid. Based on exciting preliminary studies using TTR from wallabies, we have identified a new potential mechanism of human TTR amyloid formation. In this project, we will use mutants of human and wallaby TTRs to test our hypothesis. Understanding the mechanisms of TTR amyloid formation will allow development of effective therapies in the future. This project is in collaboration with K. Altland (Giessen).
2. Regulation of neural stem cell cycle by thyroid hormones
Thyroid hormones are fundamentally involved in the regulation of growth and development, particularly of the brain. Thyroid hormones are required for normal activity of neural stem cells in adult mammalian brains. As TTR synthesis and secretion by the choroid plexus is involved in the transport of THs across the blood-brain barrier into the cerebrospinal fluid, we are investigating the regulation of neural stem cell cycle in the subventricular zone of adult TTR null mice. In TTR null mice, the level of apoptosis (programmed cell death) was as low as that in brains of hypothyroid wild type mice. We are investigating the fate of cells that would normally have undergone apoptosis. This project is in collaboration with B. Demeneix (Paris) and S. Petratos (Monash University).
3. Spinal cord regeneration
A 42-day-old Monodelphis
Spinal cord injury can result in paraplegia or quadriplegia due to the lack of regenerative capabilities of the adult central nervous system. Patients are typically young risk takers, who, with improved medical care, now have near normal life expectancy. However, the cost burden on families is enormous. We have established a model for spinal cord regeneration using the marsupial Monodelphis domestica. Following complete transection in 7-day-old Monodelphis, significant repair occurs. This ability is lost as the animal matures.
The aim of this project is to identify proteins which are differentially synthesised in the brain and spinal cord of regenerating versus non-regenerating spinal cords of Monodelphis domestica. This project is a collaboration with Professors N. Saunders and K. Dziegielewska (Univ. Melbourne).
4. Evolution of transthyretin (TTR) structure and function
Crystal structure of Salmonella dublin Transthyretin-Like Protein
The primary structure of TTR changed very little during vertebrate evolution. This implies that the TTR gene evolved prior to the divergence of vertebrates from invertebrates. The recent completion of sequencing of several genomes allowed us to use a range of bioinformatics programs to search for TTR-like genes in genomes of a wide variety of invertebrate species. We found about 80 TTR-like genes in genomes from bacteria, plants and invertebrate animals. We have shown that TTR-like protein (TLP) genes are transcribed in a bacterium (E. coli), a worm (C. elegans) and a plant (A. thaliana). TLPs have almost identical structures to TTRs, but do not bind thyroid hormones. We have identified S. dublin TLP as being a 5-HIUase, involved in uric acid degradation. Thus, TLP/TTR is an excellent model for the study of evolution of protein structure-function relationships, as its structure has not changed, but its function has.
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