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
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.
The Role Of The Inositol Polyphosphate 4-phosphatase In Cellular Signalling
Funder
National Health and Medical Research Council
Funding Amount
$454,500.00
Summary
Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell growth, cell division and other specialized functions. These cellular responses are dependent on the generation of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane compartments are called phosphoinositides. We plan to i ....Cells respond to hormones, stress, growth factors and other environmental stimuli resulting in secretion, cell growth, cell division and other specialized functions. These cellular responses are dependent on the generation of intracellular signals that send messages either to the nucleus, the cytoskeleton or membrane compartments and thereby elicit a specific response. A specific subset of signalling molecules that are localized on membrane compartments are called phosphoinositides. We plan to investigate the role of a specific lipid called PtdIns(3,4)P2 that recruits signalling proteins to specific cellular membranes including the inner wall of the plasma membrane and vesicles found within the cell. We have identified and are currently characterizing a novel enzyme called the inositol polyphosphate 4-phosphatase that terminates the signals generated by PtdIns(3,4)P2. We are characterizing mice which lack this enzyme. 4-phosphatase deficient mice demonstrate significant abnormalities in the brain and bone marrow. These mice appear unable to make circulating platelets, small anucleate cells which are vital in preventing bleeding. We will determine how the 4-phosphatase functions in regulating platelet production, by examining the bone marrow and blood of these mice. These studies are significant as platelet production is essential for prevention of blood loss following trauma and also is of vital importance in conditions associated with blood clotting including heart attack and stroke. Secondly we have identified a related enzyme to the 4-phosphatase designated P-Rex-1 which is highly expressed in brain and nerve cells. This proposal aims to determine if P-Rex-1 promotes nerve development.Read moreRead less
Biological And Clinical Characterisation Of Human Phosphatidylinositide 3-kinase Mutations
Funder
National Health and Medical Research Council
Funding Amount
$553,776.00
Summary
Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact ....Colorectal and breast cancers are the two most common registrable cancers in Australia and are second only to lung cancer in the total number of cancer deaths each year (4,678 and 2,612 deaths in 1997 for colorectal and breast, respectively). Ovarian cancer kills a further 740 women each year (Source: Cancer in Australia 1997, AIHW and AACR 2000). Thus, on average, one Australian dies of colorectal, breast or ovarian cancer every hour! Clearly, these are major diseases with a significant impact on our society. Unfortunately, though, we still do not understand the basic molecular and-or biochemical abnormalities that initiate and-or drive the development of these cancers. Our laboratory has recently reported a high frequency of mutation of the phosphoinositide 3-kinase (PI3K) gene PIK3CA in breast, colorectal and ovarian tumours. This work, funded by the NHMRC, has not only confirmed that PI3K is a bone fide human oncogene but also that mutations in the PI3K family of genes are one of the most common, and thus potentially one of the most important, genetic abnormalities in solid human tumours. In the current proposal, we aim to extend and complement our genetic studies by addressing the biological consequences and clinical significance of the mutations we have identified. This will provide crucial new insights into the biology of human tumourigenesis and further our understanding of the critical pathways and processes involved in the initiation and progression of human tumours. Such knowledge will help us to identify novel markers for diagnosis, prognosis and the early detection of cancer and enable a rational approach to the design of new anti-cancer therapies.Read moreRead less
CHARACTERISATION OF A NOVEL REGULATOR OF PHOSPHOINOSITIDE 3-KINASE-MEDIATED CELL PROLIFERATION AND PLATELET SIGNALLING
Funder
National Health and Medical Research Council
Funding Amount
$500,091.00
Summary
Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to inf ....Critical functions such as cell growth, cell death and metabolism, are tightly controlled by key proteins which respond to specific stimuli. Perturbation of this process may lead to uncontrolled growth and cancer. This project proposes to examine the potential of a novel protein (an enzyme) as a physiological regulator of cell growth. It is proposed that this enzyme may function as a brake in preventing the evolution of a cancerous state. We will also study the ability of the novel enzyme to influence other diverse functions, such as uptake of glucose, and blood clot initiation.Read moreRead less
The Role Of PIPP In Cell Polarization And Proliferation.
Funder
National Health and Medical Research Council
Funding Amount
$533,828.00
Summary
Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. 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. Following growth factor stimulation, P ....Normally cells only divide when they receive a stimulus such as from a hormone or growth factor. Upon stimulation, a series of signals are generated inside the cell which lead to cell division and development. 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. Following growth factor stimulation, PI3-kinase generates a molecule known as PtdIns(3,4,5)P3 which leads to the activation of many proteins in the signaling pathway. All cells which have PI3-kinase also have enzymes which act to switch off the signals generated by PI3-kinase and thus may play a role in preventing cancer and regulating cell development. We have identified a new enzyme known as PIPP and have shown that it acts to switch off the signals generated by PI3-kinase. We plan to investigate the role of PIPP by increasing or decreasing the amount of PIPP in cells and analysing the effects on cell growth and development. We have also identified a number of proteins which bind to PIPP and we will investigate the role these proteins play in regulating cell signaling. In addition, we plan to characterize the function of PIPP in a whole animal by generating mice which lack PIPP (knockout mice) and assessing the effects on development and cancer.Read moreRead less