Spatial And Temporal Dimensions Of Mu-opioid Receptor Signalling: Implications For The Development Of Tolerance
Funder
National Health and Medical Research Council
Funding Amount
$799,316.00
Summary
The use of morphine as an analgesic is still limited by undesirable side effects such as tolerance. Despite decades of research, the mechanisms behind the development of tolerance are poorly understood. The ? opioid receptor is a protein expressed at the surface of the cells that is the target of morphine. This project will investigate the signalling events triggered by opioids with unprecedented resolution and will aim to elucidate why morphine elicits more tolerance than other opioid drugs.
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
Colon Cancer: Receptors, Signalling And Therapeutics
Funder
National Health and Medical Research Council
Funding Amount
$7,115,542.00
Summary
This program aims to understand the biochemical and biological basis of colorectal cancer, a major cause of cancer deaths in Australia. The Chief Investigators have extensive experience in the analysis of the molecular defects in colorectal cancer cells and have already developed new drugs to treat successfully experimental colon tumours in animals. During this research program, we will explore these systems further, concentrating on the identification of novel inhibitors of colon cancer cell gr ....This program aims to understand the biochemical and biological basis of colorectal cancer, a major cause of cancer deaths in Australia. The Chief Investigators have extensive experience in the analysis of the molecular defects in colorectal cancer cells and have already developed new drugs to treat successfully experimental colon tumours in animals. During this research program, we will explore these systems further, concentrating on the identification of novel inhibitors of colon cancer cell growth, survival and movement. Newly developed instruments and techniques will allow us to identify and detect the critical steps during the development of colorectal cancer and to design potent drugs to fight the disease. We have experience in conducting novel clinical trials in colon cancer and have developed imaging techniques for monitoring the effectiveness and safety of new anti-cancer drugs. Our collective scientific experience and ability to work in the clinic provides a unique opportunity for developing more effective treatments for colorectal cancer patients.Read moreRead less
Structural And Functional Analysis Of Oncostatin M Receptor Signalling Complexes
Funder
National Health and Medical Research Council
Funding Amount
$519,284.00
Summary
Understanding how a chemical messenger selectively controls bone formation may lead to development of new therapies for osteoporosis and potentially other important diseases.
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
Mitochondrial Quality Control In Parkinson’s Disease: The Molecular Mechanisms Of PINK1 And Parkin
Funder
National Health and Medical Research Council
Funding Amount
$558,721.00
Summary
Parkinson’s disease is a degenerative disorder of the central nervous system in which the underlying cause is mostly unknown. To pave the way to a better understanding of what goes wrong, this study will investigate the function of PINK1 and Parkin, two genes that are mutated in inherited forms of the disease that play important roles in maintaining cellular health. The results of this study will be used in exploring new therapeutic targets for the treatment of Parkinson’s disease symptoms.
Molecular Characterisation Of The DBHS Proteins In Telomerase Assembly
Funder
National Health and Medical Research Council
Funding Amount
$686,246.00
Summary
Telomerase is an enzyme that is active in over 90% of cancers. Telomerase activity allows cancer cells to divide an indefinite number of times. We have identified a novel role for the DBHS protein family in regulating telomerase activity. We aim to investigate the mechanisms by which these proteins function to assemble and transport telomerase to its site of action in the cell. We then aim to develop chemical inhibitors of these proteins, and test their utility in preventing cancer cell growth.