Investigation Of Activating Signals Transmitted During Platelet Aggregation
Funder
National Health and Medical Research Council
Funding Amount
$267,750.00
Summary
The blood platelet is a specialized adhesive cell that plays a critical role in the normal blood clotting process through its ability to rapidly adhere to sites of vascular damage. Upon injury to a blood vessel, platelets undergo a number of internal signalling process and strucural changes that allow them to rapidly adhere to the area of damage. Following this initial adhesion process, platelet-platelet interactions occur leading to the development of a stable blood clot. Our research studies a ....The blood platelet is a specialized adhesive cell that plays a critical role in the normal blood clotting process through its ability to rapidly adhere to sites of vascular damage. Upon injury to a blood vessel, platelets undergo a number of internal signalling process and strucural changes that allow them to rapidly adhere to the area of damage. Following this initial adhesion process, platelet-platelet interactions occur leading to the development of a stable blood clot. Our research studies are aimed at understanding more closely the factors that regulate platelet-platelet interactions during the course of blood clot formation, since this is an important determinant not only of normal clot formation, but also in the development of harmful blood clots (thrombi) associated with the onset of diseases such as heart attack and stroke. Our particular focus is on the way in which platelets communicate to one another during the course of platelet thrombus development. Particulary, we are interested in the role of calcium as a signal mediating platelet-platelet communication. We believe that the transmission of these calcium signals may be the key signaling mediator of blood clot formation and normal haemostasis.Read moreRead less
Adhesion between cells is important during health and disease. Cell-cell interactions are necessary both as the embryo forms and to preserve tissues and organs in later life. Important disease states arise when cell-cell adhesion is broken. Only by understanding the molecular mechanisms that hold cells together can we analyse how they are perturbed to cause diseases such as cancer and inflammation.
Regulation Of Dynamic Cell-cell Adhesions By Coordinated Action Of Lipid Kinases And Phosphatases
Funder
National Health and Medical Research Council
Funding Amount
$529,565.00
Summary
This research project studies the molecular mechanisms that allow cells to attach to, and recognize, one another. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside on the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, to adhere to each other. By this means, populations of individual cells can be linked together into cohesive populations - i.e. the tissues and organs of the body. The importance of cadherin adhesion i ....This research project studies the molecular mechanisms that allow cells to attach to, and recognize, one another. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside on the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, to adhere to each other. By this means, populations of individual cells can be linked together into cohesive populations - i.e. the tissues and organs of the body. The importance of cadherin adhesion is exemplified by the fact that disruption of cadherin adhesion contributes to many important diseases, especially inflammation and cancer. Thus understanding how cadherins hold cells together is necessary for us to understand the molecular basis of common diseases. In this project we study how cadherins signal to regulate cellular behaviour. We build on our recent discovery that E-cadherin can activate a lipid in the cell membrane, PIP3, that is known to be a key regulator of many cellular activities. We aim to understand how this signal is generated in response to E-cadherin adhesion and how it elicits normal cellular responses to cadherin adhesion.Read moreRead less
Preserving Barriers: How Cadherin Signaling Coordinates Dynamic Adhesion And Tight Junction Assembly In Epithelial Cell.
Funder
National Health and Medical Research Council
Funding Amount
$557,939.00
Summary
Epithelia protect the body from its environment. Breakdown of the epithelial barrier in tissues such as the skin and intestine, as occurs in burns and inflammation, leads to invasion of bacteria and severe metabolic disturbances. In this project we study the cell signaling mechanisms that maintain epithelial barriers in healthy tissues that undergo turnover and remodelling. Understanding these signaling pathways provides a foundation to understand how they are perturbed in disease.
Molecular Characterization Of E-cadherin-activated Rac Signaling
Funder
National Health and Medical Research Council
Funding Amount
$220,500.00
Summary
Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule, E-cadherin, is a major protein that controls interactions between cells in epithelial tissues (e.g. breast, lung, gut). E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to the progression of many human cancers (especially common cancers such as breast and lung). Understanding how E-cadherin controls normal epithelial c ....Interactions between cells and their neighbouring cells control many important processes in the body. The adhesion molecule, E-cadherin, is a major protein that controls interactions between cells in epithelial tissues (e.g. breast, lung, gut). E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to the progression of many human cancers (especially common cancers such as breast and lung). Understanding how E-cadherin controls normal epithelial cell function will therefore provide key insights into the bases for tumor progression. In this study we will examine how E-cadherin signals to the interior of cells. We have recently discovered a new signaling pathway that is turned on when E-cadherin is activated. Understanding the fundamental elements of this signaling pathway will provide invaluable insights into how cells recognize one another during health and disease.Read moreRead less
Functional Characterization Of A Signaling Complex Between Receptor Protein Tyrosine Phosphatase-k And E-cadherin.
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Contact between cells in the body controls many aspects of cellular function, including cell adhesion, cell movenments, and the architecture of organs. These contacts involve many different kinds of molecules, such as adhesion molecules, proteins that link the cell surface to the cytoskeleton, and many signaling molecules that participate in cellular recognition. It has become increasingly clear that these different molecules interact with one another and that these interactions are functionally ....Contact between cells in the body controls many aspects of cellular function, including cell adhesion, cell movenments, and the architecture of organs. These contacts involve many different kinds of molecules, such as adhesion molecules, proteins that link the cell surface to the cytoskeleton, and many signaling molecules that participate in cellular recognition. It has become increasingly clear that these different molecules interact with one another and that these interactions are functionally important. In this proposal we will study the association between a signaling molecule, the receptor tyrosine phosphatase RPTPk, and a cell-cell adhesion molecule, E-cadherin. RPTPk removes phosphate molecules from tyrosines, an important event that controls many signaling processes; E-cadherin is a major adhesion molecule responsible for cell-cell contact and patterning, and whose dysfunction is involved in tumor invasion. My collaborators and I have recently demonstrated that RPTPk and E-cadherin bind to one another, but the function of this association is unclear. I will test the general hypothesis that these molecules form a signaling complex, that can regulate both the activity of RPTPk and the adhesive function of E-cadherin to ultimately control the way in which cells associate with one another. This work will make an important contribution to our understanding of how cells signal to one another, and provide insights into how cell-cell adhesion and recognition may be perturbed in disease conditions, such as tumor progression.Read moreRead less
Tetraspanins Serve As Molecular Facilitators To Regulate Platelet Thrombus Formation
Funder
National Health and Medical Research Council
Funding Amount
$589,544.00
Summary
Platelets are small fragments of megakaryocytes that circulate in the blood stream. They play an important role in preventing excessive blood loss at sites of tissue injury by sticking together and forming a haemostatic plug. Excessive platelet clumping in diseased blood vessels can lead to blockages and cause thrombotic diseases such as heart attack and stroke. We have discovered that tetraspanins serve to regulate platelet glycoproteins including integrin alphaIIbbeta, P2Y12 and thrombosis.
Loss Of Cytostatic Regulation By TGF-beta During EGFR-driven Tumor Development
Funder
National Health and Medical Research Council
Funding Amount
$605,031.00
Summary
Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulato ....Growth factor and cytokine signalling networks control many aspects of cell behaviour such as proliferation, survival, migration, invasive capabilities, transformation and differentiation. In normal cells, these complex signalling pathways are tightly regulated. Alterations of these signals are often found to cause, directly or indirectly, tumour formation. Transforming Growth Factor-b (TGF-b) and Epidermal Growth Factor (EGF) signalling pathways are both independently implicated as key regulators in tumour formation and as such they are potential therapeutic targets. However, while both pathways have been studied extensively, little is known about the cross-talk between the TGF-b and EGF pathways. This project will establish the generality of a new tumor signaling axis, namely EGFR-Stat3-Smad7-TGF-b in EGFR-overexpressing tumors. Practically, it will provide guidelines for the development of new approaches for treating effectively the EGFR-driven tumors.Read moreRead less
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less