An X-ray Crystallographic Investigation Into The Structural Basis Of T-cell Allorecognition
Funder
National Health and Medical Research Council
Funding Amount
$441,000.00
Summary
X-ray crystallography is an essential tool for solving the three-dimensional (3-D) structure of proteins. Proteins control the biological processes within the cell and it is the exact shape of proteins that determines how they function. Each protein is made up like a string of beads, with the building units being amino acids. Depending on the sequence of the amino acids, the protein molecule bends and forms a distinct, complex shape. This three dimensional shape allows it to specifically interac ....X-ray crystallography is an essential tool for solving the three-dimensional (3-D) structure of proteins. Proteins control the biological processes within the cell and it is the exact shape of proteins that determines how they function. Each protein is made up like a string of beads, with the building units being amino acids. Depending on the sequence of the amino acids, the protein molecule bends and forms a distinct, complex shape. This three dimensional shape allows it to specifically interact with carbohydrates, other proteins, such as enzymes or receptors, or even with molecules like DNA, to have its effect. To determine how a protein acts, it is vital to know the precise three-dimensional shape of a protein at the atomic level. This work is focused on understanding the precise shape of proteins that control the immune system. The immune system is avital process whereby individuals can fight off disease. This work will further our understanding of the immune system.Read moreRead less
The Role Of RYK And Eph Receptors In Developmental And Tumour Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$196,527.00
Summary
The formation of blood vessels (angiogenesis) is a key process in development of the embryo, wound healing, tumour formation-metastases and in the re-vascularisation of ischeamic limbs. The molecules which control these processess are slowly being characterised. In general belong to a family of molecules called growth factors and theri associated receptor present on the surface of a cell. These molecules can control the number, location and function of specific blood vessels within the body. Rec ....The formation of blood vessels (angiogenesis) is a key process in development of the embryo, wound healing, tumour formation-metastases and in the re-vascularisation of ischeamic limbs. The molecules which control these processess are slowly being characterised. In general belong to a family of molecules called growth factors and theri associated receptor present on the surface of a cell. These molecules can control the number, location and function of specific blood vessels within the body. Recently we have discoverd new members of a family of growth fcators called vascular endothelial growth factors, and demonstrated their ability to promote the growth of blood and lymphatic vessels. In this study we set out to examine the role of another family of growth factor receptors, called RYK (for which we have a granted patent in the USA and Australia) in angiogenesis. functional experiments in mice have demonstrated that RYK can associated with a family of receptors called Eph receptors which play a key role in the remodelling of blood vessels during development and injury. Studying these molecules may tell us why blood vessels know' to be in the correct locations in the body and why in certain disease we see vessels of incorrect structure or location. These studies will form a basis of knowledge to develop rational means to manipulate blood vessel formation in the body, using non-surgical methods. The work will also have application to the areas of cleft palate, craniofacial abnormalities and axon pathfinding.Read moreRead less
Targeting 124I To The DNA Of Tumours For PET Imaging And Auger-Radiotherapy
Funder
National Health and Medical Research Council
Funding Amount
$787,000.00
Summary
The aim of this project is to develop a new method of targeting radioactivity to tumours, for detection and treatment, using a radioactive element (iodine-124). Iodine-124 emits a form of radiation called positrons, detected by a new imaging technique - Positron Emission Tomography (PET). Therefore, tumours labelled with iodine-124 can be imaged by PET. Also, iodine-124 is amongst a class of radioactive atoms (called Auger-emitters) that emit a shower of very low energy electrons. This intense f ....The aim of this project is to develop a new method of targeting radioactivity to tumours, for detection and treatment, using a radioactive element (iodine-124). Iodine-124 emits a form of radiation called positrons, detected by a new imaging technique - Positron Emission Tomography (PET). Therefore, tumours labelled with iodine-124 can be imaged by PET. Also, iodine-124 is amongst a class of radioactive atoms (called Auger-emitters) that emit a shower of very low energy electrons. This intense focus of radiation damage, can be exploited to kill cancer cells by inflicting lethal DNA damage. To bring the iodine-124 close to the DNA molecule, we will attach it to a DNA-binding drug linked to a tumour-seeking protein, such as an anti-tumour antibody. After injection of the radioactive drug-protein cocktail, PET imaging will be used to assess the extent of tumour targeting, to enable calculation of the amount of cocktail required for successful tumour treatment by further injections. There are some situations where tumour imaging needs to be non-damaging, such as in using PET imaging to assess the success of surgical removal of a tumour. Therefore, we will design an alternative version of the iodine-124-labelled DNA- binding drug with the radioactive atom in a location that will minimise DNA damage from radioactive decay. In this imaging-only scenario, the Auger-emission feature is suppressed whilst still exploiting positron-emission for imaging. The stability of radioactive atoms varies widely, and the half-life of iodine-124 (about four days) is an ideal compromise for imaging and treatment. By contrast, the utility of the most commonly used isotope for PET imaging, fluorine-18, is limited by its half-life of only a few hours. The PET Centre at PeterMac will soon produce iodine-124, joining one of only a few centres throughout the world. Peter Mac has recently lodged a patent application for the technology to be developed in this project.Read moreRead less
Structural And Functional Analysis Of A Cancer-linked Co-regulator Complex
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
We seek to understand the mechanisms by which genes are switched on and off throughout our lifetime. A number of multi-component protein machines are involved in this process but their make-up and mechanism of action is not understood. We will investigate the structure and function of one of these machines that has been strongly linked to cancer.
Defining A Role For The STONED Proteins In The Synaptic Vesicle Cycle
Funder
National Health and Medical Research Council
Funding Amount
$301,527.00
Summary
Nerve cells communicate with each other by means of chemical neurotransmitters. The level of communication is strictly controlled, and changes in the level, either up or down, is known as synaptic plasticity. This plasticity is thought to underly changes in the brain that account for both long and short term memory. Uncontrolled alterations in plasticity can also induce abnormal brain function, resulting in neurological disorders. Changes in the release of neurotransmitter are regulated at the m ....Nerve cells communicate with each other by means of chemical neurotransmitters. The level of communication is strictly controlled, and changes in the level, either up or down, is known as synaptic plasticity. This plasticity is thought to underly changes in the brain that account for both long and short term memory. Uncontrolled alterations in plasticity can also induce abnormal brain function, resulting in neurological disorders. Changes in the release of neurotransmitter are regulated at the molecular level by unknown mechanisms, however the chemical neurotransmitters are enclosed in small vesicles and it is believed that the control of the release of these vesicles, and their recycling, are important components of this mechanism. We have identified a gene that encodes two novel proteins of neurotransmission. Mutations that alter these genes can result in either increased or decreased synaptic activity. By using a combination of genetic and molecular techniques we propose to investigate how one of these two proteins operate to alter synaptic activity, as well as attempting to show how it interacts with other components of the synaptic machinery.Read moreRead less
The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled r ....The maintenance of optimum health and function of living cells, and consequently that of the whole organism, depends on how cells respond to a multitude of physical and chemical stimuli that continually bombard them. The majority of the chemical stimuli such as hormones and neurotransmitters impart their actions not by directly entering the cell, but instead, by binding to a specific receiver protein at the cell surface called a receptor. In one class of such receptors called G protein coupled receptors, the transmission of the message to the interior of the cell involves yet another protein called G protein. It is extremely important to unravel how each of these components, the stimulating agent, the receptor and G protein, works in order to understand how the cells respond to various chemical signals. To make this process even more complex, it was recently shown that another newly discovered group of proteins called receptor activity modifying proteins (RAMPs) too play a critical role in some systems. Understanding what actually is the role of these new players, and how they team-up with the other components to elicit a specific response to a chemical stimulus, forms the basis of this proposal. Such knowledge is central to the unraveling of the processes involved in the maintenance of health, abnormalities that lead to disease, and in the development of new treatments.Read moreRead less
INVESTIGATIONS INTO THE BIOLOGICAL FUNCTIONING AND PROGNOSTIC VALUE OF NOVEL METASTATIC MARKERS FOR BREAST CANCER
Funder
National Health and Medical Research Council
Funding Amount
$423,564.00
Summary
Breast cancer is the most malignant tumour of women and, despite great advances in detection and treatment, some 30% of women who present with primary breast cancer eventually relapse or die of their disease. Genetic studies have resulted in the rapid identification of the one-third of women at high risk of developing breast cancer because of a family history of the disease: it is hoped that these women will eventually benefit from advances in gene therapy now being developed. For the majority o ....Breast cancer is the most malignant tumour of women and, despite great advances in detection and treatment, some 30% of women who present with primary breast cancer eventually relapse or die of their disease. Genetic studies have resulted in the rapid identification of the one-third of women at high risk of developing breast cancer because of a family history of the disease: it is hoped that these women will eventually benefit from advances in gene therapy now being developed. For the majority of women developing breast cancer, however, the outcome, or prognosis, remains uncertain. The most important indicators of outcome are obtained by study of the excised cancer tissue, and these relate to the speed of growth of the cancer cells and their ability to migrate, or metastasise, to other sites in the body. Studies of cancer tissue using molecular cell biological methods has enabled the identification of several markers that are proving useful as indicators of outcome, and further understanding of the biological functioning of these markers will enable these molecules to be targetted in new treatments aimed at preventing the spread of the cancer. The present study will examine the appearance of new markers for cell migration among breast cancers and measure their value as indicators of outcome. One molecule in particular may be useful as a therapeutic target since it is used by migrating cells during development but is not expressed by normal (non-cancer) adult tissue cells. Towards this, the project will seek to understand how this molecule functions in cell migration.Read moreRead less
LMO2-containing Complexes In Leukemia And Blood Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$803,652.00
Summary
Childhood T-cell leukemias have a poor prognosis for recovery. We are determining, with atomic level precision, how the proteins Lmo2 (also linked to prostate and other cancers) and Tal1, and their binding partners contribute to both normal blood cell development and T-cell leukemia. With this information we are developing reagents that can be used to disrupt disease-causing complexes, and which will lead towards the development of new, specific, therapeutics for leukemias and other cancers.