Examining The Role Of Profilin As A Regulator Of Cancer Aggressiveness
Funder
National Health and Medical Research Council
Funding Amount
$261,778.00
Summary
Cancer treatment in Australia costs ~ $2.7 billion per annum. Current mainstream treatments often cause major side effects and thus less toxic therapeutic approaches are urgently needed. Profilin has recently emerged as a promising anti-cancer target. We will investigate how cancer can be suppressed by altering the interaction between profilin and its partners (lipids, phosphoinositides, and actin). This project will provide essential groundwork for the development of novel cancer therapeutics.
Novel Upstream Regulatory And Down-stream Signaling Mechanisms Of The Src-family Protein Kinases
Funder
National Health and Medical Research Council
Funding Amount
$363,639.00
Summary
Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by thei ....Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by their native inhibitor CHK suppresses cancer formation and how over-stimulation of SFKs causes cancer. Exactly how CHK inactivates SFKs remains unclear. Recently, we discovered a novel mechanism employed by CHK to inhibit SFKs. In this mechanism, CHK binds to SFKs tightly and the binding alone is sufficient to completely shut down SFK activity. As this novel inhibitory mechanism of CHK can be exploited for the development of synthetic SFK inhibitors for cancer treatment, we propose to unravel how CHK tightly binds to SFKs and how the binding inhibits the cancer-promoting activity of SFKs. How over-stimulation of SFKs induces the development of human cancer has been an important outstanding question in cancer research. Recently, we and two groups of researchers in Texas achieved breakthroughs in answering this question. The Texan groups discovered that the over-stimulated SFKs cause cancer by shutting down the anti-tumour activity of a tumour suppressor called PTEN. We complemented their findings by discovering how SFKs shut down PTEN activity - SFKs shut down PTEN activity by a chemical modification process called phosphorylation. In this application, we propose to study how SFKs modify PTEN and how phosphorylation shuts down the tumour suppressor activity of PTEN. In summary, our studies will benefit the development of two types of anti-cancer therapeutics: (i) those mimicking CHK binding and inhibition of SFKs, and (ii) those interfering with phosphorylation of PTEN by SFKs.Read moreRead less
Discovery And Mechanisms Of Host Cell Factors In HIV Uncoating
Funder
National Health and Medical Research Council
Funding Amount
$635,098.00
Summary
HIV entry into the host cell involves release of its capsid, a protein shell protecting the viral genome. The capsid hijacks host proteins to cloak itself from cellular defenses while the cell has evolved sensors that can block viral infection. This proposal aims to discover proteins involved in this arms race between host and virus and decipher how they control capsid disassembly. This insight will help design new drugs against HIV infection and new ways to deliver genes for gene therapies.
Structural And Drug Discovery Studies Of Medically Important Protein Complexes
Funder
National Health and Medical Research Council
Funding Amount
$438,577.00
Summary
My research is focused on structural studies of medically important biological systems, where specific protein complex formation contributes to human illnesses. I use X-ray crystallography to visualize the whole complex at atomic resolution as well as to determine whether binding partners have undergone changes in shape upon complex formation. This structural information then helps me in drug design with goals to either disrupt or modulate the complex.
Role Of Hsp40 And Hsp70 In Huntingtin Misfolding, Oligomerization And Inclusion Assembly
Funder
National Health and Medical Research Council
Funding Amount
$590,103.00
Summary
Huntington disease results from a mutation that causes the Htt protein to become abnormally sticky and form toxic clusters in neurons. Cells have natural defences to clustering with proteins called chaperones, which are exciting therapeutic targets. This project will examine how chaperones defend against toxic Htt clustering with cutting-edge imaging technologies. The knowledge gained will aid in designing therapeutic strategies that stimulate the defence processes and suppress the clusters.
Disrupting Mucin-mucin Interactions To Treat Respiratory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$480,531.00
Summary
Diseases like asthma, emphysema and cystic fibrosis all feature the overproduction of mucus in the lungs that make it very difficult for patients to breathe and increases their susceptibility to infections. Few therapies are available for thinning this mucus, which is made thick by a network of linkages between proteins. We are studying these linkages and developing methods to break them up. This research could yield new mucus-thinning drugs to treat lung diseases.
Mechanisms Regulating Mitochondrial Outer Membrane Permeabilisation During Programmed Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$306,562.00
Summary
Apoptosis is a form of cell suicide that is vital in human development and health by removing damaged or unwanted cells in a regulated manner. Disturbances in this pathway are known to be the cause of cancers and other diseases. This research will investigate how the pivotal step in cell death, termed mitochondrial outer membrane permeabilisation (MOMP) is regulated.
The Role Of Apolipoprotein E In High Density Lipoprotein Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$151,208.00
Summary
Coronary heart disease is a major cause of death and disability in Australia. A high level of blood cholesterol increases the risk of developing coronary heart disease. This increase in coronary risk is caused by the cholesterol that is carried in low density lipoproteins (LDL). However, not all cholesterol is bad. A proportion of the cholesterol in blood is carried high density lipoproteins (HDL), which are powerful protectors against heart disease. People with high blood levels of HDL have a s ....Coronary heart disease is a major cause of death and disability in Australia. A high level of blood cholesterol increases the risk of developing coronary heart disease. This increase in coronary risk is caused by the cholesterol that is carried in low density lipoproteins (LDL). However, not all cholesterol is bad. A proportion of the cholesterol in blood is carried high density lipoproteins (HDL), which are powerful protectors against heart disease. People with high blood levels of HDL have a significantly reduced risk of developing heart disease. HDL consist of several different types of particles that contain lipids (or fats) and proteins. Not all HDL protect equally against coronary heart disease. Our ability to determine which HDL are the most cardioprotective is limited because it is difficult to separate the different types of particles from each other. One thing we do know is that the cardioprotective properties and metabolism of HDL are influenced by the proteins they contain. A considerable amount is known about the effects of the two main HDL proteins on the metabolism and cardioprotective properties of HDL. However, HDL contain several other proteins which are also important in this regard. This project is concerned with one of those other proteins called apolipoprotein E. The evidence that apolipoprotein E protects against heart disease is indisputable. Despite this, almost nothing is known about its role in HDL metabolism. This is because it is difficult to isolate large amounts of apolipoprotein E-containing HDL from plasma. In order to overcome these problems I have developed a novel method for preparing HDL which contain apolipoprotein E. These preparations are comparable to the apoE-containing HDL in human plasma. They will be used in this project to study the influence of apolipoprotein E on HDL metabolism.Read moreRead less
Developing Novel Molecules That Target Hormone Receptors As An Alternative Cancer Therapy
Funder
National Health and Medical Research Council
Funding Amount
$459,867.00
Summary
A promising class of cancer drugs target heat shock protein 90 (Hsp90) and prevent Hsp90 from maintaining its ~100 proteins involved in cell growth. However, all current Hsp90 chemotherapeutics non-selectively target proteins maintained by Hsp90, and induce a cell rescue mechanism involving Hsp70. We describe the development of a novel molecule that will selectively control cell growth and prevent cell rescue via a unique Hsp90 regulated mechanism.