Studies On The Role Of The P101 Component Of The Class 1B PI 3-Kinase In Cell Migration And Activation.
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
This research will determine the biological role of a protein of unknown function that is likely to participate in movement of white blood cells through the body. The outcome of this research will increase our basic knowledge of how the immune system functions and could lead to alternate therapeutic strategies for the control of autoimmune diseases.
Investigation Of A New Approach To Regulate Fibrin Clot Retraction And Arterial Thrombolysis
Funder
National Health and Medical Research Council
Funding Amount
$483,171.00
Summary
Pathological blood clots are removed in patients by administering clot dissolving drugs (fibrinolytics). However these drugs are quite often ineffective and cause bleeding. We have identified a new platelet-mediated pathway controlling contraction of blood clots, important for clot stability. In this proposal, we will examine the potential for inhibitors of this pathway to loosen blood clots, and facilitate the actions of fibrinolytics to promote clot dissolution.
Investigation Of Negative Signalling Mechanisms In Platelets
Funder
National Health and Medical Research Council
Funding Amount
$292,500.00
Summary
Platelets are specialised blood cells essential for normal blood clotting. We are studying the processes that control platelets sticking to the exposed vessel wall, to each other and to other cells to form a stable blood clot at the site of injury to stop bleeding. The same processes, when unchecked, could lead to the formation of harmful large blood clots that may block blood vessels in the heart or brain, resulting in heart attack or stroke. Platelets stick to the blood vessel wall and each ot ....Platelets are specialised blood cells essential for normal blood clotting. We are studying the processes that control platelets sticking to the exposed vessel wall, to each other and to other cells to form a stable blood clot at the site of injury to stop bleeding. The same processes, when unchecked, could lead to the formation of harmful large blood clots that may block blood vessels in the heart or brain, resulting in heart attack or stroke. Platelets stick to the blood vessel wall and each other through sticky proteins called receptors on the cell surface. Receptors are able to bind to their specific ligands such as von Willebrand factor (vWf) and collagen which become exposed following vessel wall damage. The interaction between the ligands and receptors will trigger many biochemical changes within platelets, called signal transduction, that control platelet stickiness. The aim of this research project is to investigate the signalling processes that are utilised by the major platelet receptor called integrin alpha IIb beta 3. We are particularly interested in identifying the negative signalling process utilised by this receptor to dampen the positive signals required for platelet stickiness, to achieve a balanced clotting process. The identification of these specific signalling pathways will not only increase our knowledge of blood clot formation in health and disease, but also help develop potential new therapies for the prevention of heart diseases and strokes.Read moreRead less
Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insu ....Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insulin are diminished and cells become increasingly unable to uptake glucose. Recent studies have demonstrated that a novel enzyme known as SHIP-2 may play a role in regulating insulin action in cells. Deletion of SHIP-2 in mice results in these animals have increased sensitivity to insulin, low blood glucose levels, and a greatly enhanced ability to take up glucose in cells in response to low dose insulin. Our laboratory has been working on the cellular mechanisms regulating SHIP-2 function. We have recently revealed the intracellular location of SHIP-2 and also demonstrated how SHIP-2 is localized in the cell. These studies have shown that SHIP-2, via interactions with other proteins, regulates the actin cytoskeleton immediately beneath the cell membrane and this may be a mechanism for facilitating cellular glucose uptake. This research proposal aims to determine how SHIP-2 facilitates glucose uptake into cells. We will make cell lines and transgenic animals which express high levels of this enzyme and determine the functional consequences on insulin stimulated glucose uptake. Collectively these studies in the long term may facilitate better treatment strategies for diabetic patients.Read moreRead less
Characterisation Of Autophagy Deficiency In Skeletal Muscle Homeostasis
Funder
National Health and Medical Research Council
Funding Amount
$956,237.00
Summary
Defects in skeletal muscle are a cause of muscle disease, and also have broad health implications for diabetes, obesity and liver disease. As such, it is important to understand the processes required for healthy muscle and how signals communicate from muscle to the liver and fat, which integrate whole body metabolism. This application examines how the cellular degradation process known as autophagy integrates these important processes by investigating a novel gene regulator of this pathway.
The immune system usually rapidly responds to eradicate infectious pathogens. However patients with mutations in the gene PI3KCD, which is important for delivering messages within immune cells, are unable to control infections with some bacteria and viruses. We will study the effects of these mutations on B cells, the immune cells produce antibodies that bind to and remove pathogens from our body. This will explain some of the clinical features of this disease and reveal potential new treatments
Investigation Of The Role Of PI3-kinase In The Regulation Of Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$837,660.00
Summary
The formation of blood vessels is critical for the development of embryos, but also after birth in processes such as wound healing. However, the uncontrolled formation of new blood vessels is also a feature of many human diseases such as cancer, and eye diseases that lead to blindness in adults or in premature infants. We propose to identify new regulators of blood vessel development, in order to improve current treatment therapies for these debilitating diseases.
Regulation Of PtdIns(3,4)P2 Signalling By Inositol Polyphosphate 4-phosphatase-1
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. One of the signaling pathways which responds to growth factor stimulation is the PI3-kinase pathway. This pathway has been implicated in many different human cancers which occur when cells divide uncontrollably and invade into the surrounding tissues. We have idenitified a novel enzyme called the inositol polyphosphate 4-phosphatase that appears to regulate cell proliferation and differentiation.
Regulation Of 14-3-3 Monomerisation Controls Cell Life/death Fate
Funder
National Health and Medical Research Council
Funding Amount
$524,770.00
Summary
14-3-3 proteins are becoming increasingly recognised as major multifunctional proteins that control key aspects of normal and pathological processes. Although initially viewed as inert components of signalling, we have now recognised for the first time that these are very dynamic proteins that can be regulated. Our main aim is to understand the regulatory mechanisms controlling the different dynamic forms of 14-3-3 and how each form in turn controls the process of life and death.