This work will analyse how cells, the building blocks of tissues, are organized together to form functioning organs. It focuses on the adhesion molecules that allow cells to recognize one another, which cooperate with the internal skeleton of cells to link them together. We aim to understand how these cellular systems work normally and how they are targeted to disrupt tissue integrity in diseases like cancer and inflammation.
Cortactin: Molecular Regulation Of Cadherin Activity And Epithelial Morphogenesis.
Funder
National Health and Medical Research Council
Funding Amount
$239,250.00
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 how cells interact with one another in many epithelial tissues (e.g. breast, lung, gut). These tissues are the source of many common diseases, particular cancer and inflammation. E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to disease in these tissues (especially common ca ....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 how cells interact with one another in many epithelial tissues (e.g. breast, lung, gut). These tissues are the source of many common diseases, particular cancer and inflammation. E-cadherin is essential for these tissues to form normally, and loss of E-cadherin function contributes to disease in these tissues (especially common cancers, such as breast and lung). Understanding how E-cadherin controls normal cell function in these tissues will therefore provide key insights into how disease arises. In this study we will investigate how a protein which binds to E-cadherin, cortactin, contributes to the biological effect of E-cadherin in supporting tissue architecture. Understanding the fundamental elements of how cortactin works with E-cadherin will provide invaluable information into how cells recognize one another in health, and fail to adequately recognize each other in common diseases.Read moreRead less
MicroRNAs are small molecules that modulate the expression of most genes and so affect nearly every biological process and pathology although, they were only discovered in humans less than 10 years ago. The bottleneck in discovering the functions of miRNAs is in identifying their molecular targets, the majority of which remain unknown. We aim to comprehensively identify direct target genes of epithelial-specific microRNAs and to confirm a number of them by gene target validation approaches.
Role Of The MiR-200 Target Quaking In Alternative Splicing During EMT And Cancer Progression
Funder
National Health and Medical Research Council
Funding Amount
$443,160.00
Summary
The spread of cancer to other organs involves cancer cells changing to a more aggressive state and is a major cause of cancer related death. MicroRNAs are a class of genes that control whether cancer cells become more aggressive by regulating other genes. In this project we will examine the function of a new microRNA target which controls the cancer cell aggression. The outcome will be a better understanding of how cancers spread and the identification of new therapeutic targets.
Microenvironmental Regulation Of The Tissue Regenerative Capacity Of Keratinocyte Stem Cells And Their Progeny.
Funder
National Health and Medical Research Council
Funding Amount
$391,762.00
Summary
The protective outer layers of the skin known as the epidermis belongs to a group of tissues in the body that are turning over at a rapid rate. The majority ofepidermal cells have a lifespan of just 2-3 weeks, and are shed as mature cells from the skin's surface. These cells are replaced by continuous cell regeneration which is dependent on growth factors and adhesive molecules (and other signals). It has recently come to light that the connective tissue of the skin i.e. the dermis, which lies d ....The protective outer layers of the skin known as the epidermis belongs to a group of tissues in the body that are turning over at a rapid rate. The majority ofepidermal cells have a lifespan of just 2-3 weeks, and are shed as mature cells from the skin's surface. These cells are replaced by continuous cell regeneration which is dependent on growth factors and adhesive molecules (and other signals). It has recently come to light that the connective tissue of the skin i.e. the dermis, which lies directly below the epidermal cells has a critical role in providing some of these factors required for their growth and maturation. Indeed, it is becoming increasingly clear that the epidermal and dermal cells co-operate to regulate epidermal proliferation and maturation. Recent work from our laboratory has shown that a newly recognised adhesive protein laminin-10 may be produced as the result of such co-operation and that it stimulates the growth of both normal and tumour epidermal cells. We have also recently identified an interesting subset of dermal cells that may have a role in promoting the growth of the epidermal cells. Thus, the aims of the proposed stuides are to investigate the role of laminin-10 and this specific dermal cell subset in epidermal proliferation and maturation. These studies may also provide an insight into the role of these factors in skin cancers.Read moreRead less
Microtubule Capture By E-cadherin: A Novel Mechanism For Dynamic Cell-cell Adhesion.
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified ....This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified by the well-documented observation that disruption of cadherin adhesion contributes to many important diseases, including inflammation of epithelia and cancers. Thus understanding the mechanisms by which cadherins hold cells together is necessary for us to understand the molecular basis of commondisease. It has long been known that cadherins work in cooperation with elements within the cell, called the cytoskeleton. My lab has recently made the novel discovery that microtubules, specific components of the cytoskeleton, can regulate the functionof cadherin adhesion molecules. Inparticular, microtubules appear to affect how cadherins can participate in dynamic cell processes necessary for cells to be properly organized in tissues. In this project we will probe the molecular mechanisms responsible for this effect of microtubules. The information obtained will provide important new insights into how dynamic cadherin adhesion is controlled, to help our understanding of the cellular mechanisms that couple cells into tissues, and how they may be disrupted in diesase.Read moreRead less
Idiopathic pulmonary fibrosis (IPF) is a fatal disease of unknown cause which is unresponsive to current therapy. This study builds on recent work by this group highlighting the importance of a cell signalling molecule called STAT3 in the development of this disease. In particular, two cell types that utilise STAT3 signalling, epithelial cells and B cells, will be examined to see if blocking their STAT3 responses could be a novel therapeutic approach.
Regulation Of The Activity And The Surface Expression Of Sodium Channels
Funder
National Health and Medical Research Council
Funding Amount
$466,980.00
Summary
The regulation of transport of salt into and out of the body is essential for the maintenance of blood pressure, and for the maintenance of the correct amount of fluid in the respiratory passages and gut. A critical component of the mechanism by which the body transports salt are sodium channels. Overactivity of these channels leads to increased blood pressure and clogging of the gut and the bronchi due to thick and sticky secretions. Reduced activity leads to abnormally low blood pressure, as w ....The regulation of transport of salt into and out of the body is essential for the maintenance of blood pressure, and for the maintenance of the correct amount of fluid in the respiratory passages and gut. A critical component of the mechanism by which the body transports salt are sodium channels. Overactivity of these channels leads to increased blood pressure and clogging of the gut and the bronchi due to thick and sticky secretions. Reduced activity leads to abnormally low blood pressure, as well as to accumulation of fluid in the lungs such as occurs in influenza and in altitude sickness. The present project will examine the mechanisms by which sodium channels are regulated. It will particularly focus on the mechanisms by which sodium channels are switched off when the salt content of cells is too high.Read moreRead less
Preserving Junctions: Regulating Cadherins By Rho And Myosin 2.
Funder
National Health and Medical Research Council
Funding Amount
$425,500.00
Summary
This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified ....This project studies the molecular mechanisms responsible for holding cells together in normal tissues. Such cell-to-cell adhesion is mediated by the cadherin family of molecules, which reside at the surfaces of cells. Cadherins allow cells to recognize one another and, upon recognition, adhere to one another. By this means populations of individual cells can be linked together into cohesive populations (i.e. the tissues or organs of the body). The importance of cadherin adhesion is exemplified by the well-documented observation that disruption of cadherin adhesion contributes to many important diseases, including inflammation of epithelia and cancers. Thus understanding the mechanisms by which cadherins hold cells together is necessary for us to understand the molecular basis of commondisease. Characteristically, cadherins accumulate in structures called adherens junctions, and preserving those junctions is important both for tissues to organize and also to prevent tumor progression. Despite this, we know very little about how junctions are preserved in epithelia. The research to be conducted in this grant will examine exactly this problem. It builds upon recent findings from my lab which indicate that the motor molecule, myosin 2 plays an essential role in preserving junctions. Furthermore, we will test the role for signaling pathways within cells to control the activity of myosin 2 at junctions. This research will provide important novel insights into the cellular mechanisms that couple cells into tissues, and how they may be disrupted in diesase.Read moreRead less