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.
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.
Structural And Biochemical Investigation Of The Bloom�s Complex, Defective In Bloom�s Syndrome
Funder
National Health and Medical Research Council
Funding Amount
$184,661.00
Summary
Bloom�s Syndrome is a rare inherited disorder that results in greater than 90% risk of developing cancer by the age of 25. The gene that causes Bloom�s Syndrome, called BLM, protects cells from cancer-causing mutations hence affected individuals develop the same types of cancers as the general population, only much faster. We will investigate the properties of the BLM gene product and understand how it protects us from cancer, and may influence some forms of cancer treatment.
Transcriptional Complexes In Haematopoiesis And T-cell Leukemia
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
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.
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
Analysis Of APC And APC Protein Complexes In Colon Cancer
Funder
National Health and Medical Research Council
Funding Amount
$110,786.00
Summary
Colorectal cancer is one of the foremost causes of death in Australia. A defective form of a protein called APC has been shown to be present in more than 80% of colon tumours. How APC contributes to colon cancer is still not known. We aim to determine the function of the APC protein by studying the APC protein and proteins that interact with APC in normal and cancerous colon epithelial cells. We will use cells derived from normal colon epithelium as well as from colon carcinomas. Once we have id ....Colorectal cancer is one of the foremost causes of death in Australia. A defective form of a protein called APC has been shown to be present in more than 80% of colon tumours. How APC contributes to colon cancer is still not known. We aim to determine the function of the APC protein by studying the APC protein and proteins that interact with APC in normal and cancerous colon epithelial cells. We will use cells derived from normal colon epithelium as well as from colon carcinomas. Once we have identified proteins that interact with APC in normal colonic cells, we will have a more complete understanding of the function of APC and its role in the development of colonic tumours.Read moreRead less
Engineered Histones As DNA Carriers With Application In Therapeutic Gene Delivery
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy ....We intend to apply our knowledge of protein transport to the nucleus to enhance the delivery of DNA to target cells. This relates to the use of gene therapy to treat genetic defects such as inborn errors of metabolism, where a disease-causing lack-of-function mutation can be overcome by engineering cells within the organism which express, in the necessary quantities and in response to the appropriate regulatory signals, the particular component which is lacking. A limiting factor in gene therapy approaches is the low efficiency of nuclear uptake of introduced DNA, where it has been estimated that < 1% of the DNA taken up is actually expressed. Our proposal seeks to develop approaches to enhance non-viral-mediated gene delivery, in particular by optimising this critical, limiting step of the delivery of exogenous DNA to the nucleus. We intend to apply knowledge from studies of nuclear targeting and chromatin assembly to improve gene transfer technologies. We will build on our work showing that specific signals for nuclear import - nuclear targeting signals (NTSs) - can be used to enhance nuclear gene delivery and expression. Since DNA in the normal cellular context is in the form of chromatin - a specific complex with proteins such as histones - we intend to use reconstituted chromatin as the transfecting DNA, whereby histones engineered to include NTSs and other modular sequence elements will be used. Chromatin should not only enable NTSs and other sequence modules to be linked to the DNA but also protect against nuclease-mediated degradation prior to nuclear entry, condense the DNA to enable more efficient cellular-nuclear entry, and ensure expression of the transfected reporter gene by presenting it to the cell in a physiological context. Our approaches should contribute to bringing gene therapy closer to reality in the clinic.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
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