Elucidating Mechanisms For The Biological Activities Of CD46.
Funder
National Health and Medical Research Council
Funding Amount
$228,000.00
Summary
The CD46 protein enables entry into cells of a number of different pathogens, including the measles virus, Neisseria meningitidis (the major cause of meningococcal disease), Neisseria gonorrhoea, Human Herpes Virus 6, and group A streptococcus. In addition, by binding to a key blood component that is often attached to foreign pathogens, CD46 can facilitate binding and entry of other pathogens. As well as facilitating entry of the pathogen, it has recently become apparent that CD46 binding trigge ....The CD46 protein enables entry into cells of a number of different pathogens, including the measles virus, Neisseria meningitidis (the major cause of meningococcal disease), Neisseria gonorrhoea, Human Herpes Virus 6, and group A streptococcus. In addition, by binding to a key blood component that is often attached to foreign pathogens, CD46 can facilitate binding and entry of other pathogens. As well as facilitating entry of the pathogen, it has recently become apparent that CD46 binding triggers a wide range of responses from the human host. Some of these responses are likely to further facilitate survival and proliferation of the pathogen, but others are more likely to facilitate host defence. For examples, signals triggered by binding to CD46 can both abrogate some aspects of the immune response (and it is though that this immunosuppression contributes to the secondary infections that cause the death of nearly one million children each year) and facilitate other aspects of the immune response. By understanding the mechanisms by which CD46 triggers these complex responses, we firstly be able to dissect how important each of these processes are to the overall pathogenecity of the virus or bacteria. Furthmore, this understanding will allow us to design better vaccines and drugs to combat these diseases.Read moreRead less
This program of research is firmly focussed on the basic mechanisms involved in normal functioning of cells and tissues, followed by a step by step process to understand the abnormal or the diseased. The disease states we are investigating involve the blood and blood vessels, and when there is malfunction it may contribute to conditions as diverse as atherosclerosis, thrombosis, inflammation and cancer. The program thus addresses the fundamentals of diseases which are responsible for most deaths ....This program of research is firmly focussed on the basic mechanisms involved in normal functioning of cells and tissues, followed by a step by step process to understand the abnormal or the diseased. The disease states we are investigating involve the blood and blood vessels, and when there is malfunction it may contribute to conditions as diverse as atherosclerosis, thrombosis, inflammation and cancer. The program thus addresses the fundamentals of diseases which are responsible for most deaths in our society. We will use technology which is proven to provide precise information, the molecular and biochemical processes responsible for cell function (or malfunction). However in each individual project there will be a clear path to a clinical use, diagnostic or therapeutic. Indeed in a number of the components of the program there are already potential treatments and diagnostics in development and trial.Read moreRead less
Transcriptional Regulation Of The Complement Receptor 2 Gene (CR2/CD21) During B Cell Lineage Committment
Funder
National Health and Medical Research Council
Funding Amount
$466,500.00
Summary
The complement system is a very important pathway within the human immune system. One of the receptors within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the inflammatory response and defence against microbes but is also important in normal generation of a B cell immune response . B cells not only produce antibodies against foreign organisms but in some cases dysfunction of the B cell can bring about autoimmunity by production of antibodies aga ....The complement system is a very important pathway within the human immune system. One of the receptors within this system is complement receptor 2 or CR2. CR2 has not only been shown to be important within the inflammatory response and defence against microbes but is also important in normal generation of a B cell immune response . B cells not only produce antibodies against foreign organisms but in some cases dysfunction of the B cell can bring about autoimmunity by production of antibodies against self tissues and cells . How the CR2 gene turns on expression on different cells within the immune system is complex. The amount of receptor on the surface of antibody producing B cells has important implications to B cell biology. As CR2 expression is turned on at an important point within the antibody producing B cell and the levels of this receptor can influence B cell function, understanding how this gene is regulated is important.Read moreRead less
Characterisation Of Notch Asparaginyl Hydroxylation By FIH-1.
Funder
National Health and Medical Research Council
Funding Amount
$307,841.00
Summary
Cells within our body receive numerous signals telling them when to grow, when to turn into another cell type and exactly what type, and even how to respond to situations like low oxygen. These signals and cells response are very important during embryonic development, when these signals cause a single cell to become a complete person, and also in adults. Here in the embryo, and also in adults, stem cells are very important because they can become many different kinds of cells, depending on what ....Cells within our body receive numerous signals telling them when to grow, when to turn into another cell type and exactly what type, and even how to respond to situations like low oxygen. These signals and cells response are very important during embryonic development, when these signals cause a single cell to become a complete person, and also in adults. Here in the embryo, and also in adults, stem cells are very important because they can become many different kinds of cells, depending on what the body needs. When the signals don't work properly, they cause major problems and diseases, from birth defects, to cancer. Notch is an important protein involved in receiving and passing on certain signals, and is found in organisms as diverse as worms and humans. It tells cells, especially stem cells and other similar cells, when and how to change from one type of cell to another. For example, it is very important in the generation of many different types of blood cells from a single precursor cell. Notch has also been implicated in human diseases such as cancer, where signalling goes wrong and cells keep multiplying out of control, and also certain types of heart disease. Another protein, called FIH, is an oxygen sensor that signals to the cell when there is not enough oxygen around. FIH has also been implicated in cancer and heart disease. We have recently found evidence suggesting that FIH can also influence the activity of the Notch proteins. This means that oxygen levels can potentially have an effect on stem cells and other processes controlled by Notch, and may be very important in cancer and other diseases. This project will first confirm the connection between FIH and Notch. There are a number of different Notch proteins, so we will see if this connection works with all of them. It will also try and work out the consequence of this connection is and how important it is. Finally, the likely biological consequences on human diseases, specifically cancer.Read moreRead less
REGULATION OF MICROTUBULE DYNAMICS BY LIM KINASE1 (LIMK1)
Funder
National Health and Medical Research Council
Funding Amount
$386,020.00
Summary
Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. We have found that LIMK1 is very important in controlling the polymerisation of one of the most ....Disseminated cancer, unlike the localized disease, can rarely be cured by drug therapy. We have found that LIM kinase (LIMK1), a protein that was discovered in our laboratory, plays an important role in controlling the ability of tumour cells to spread, a process called metastasis. Thus, this protein becomes an important target for the development of new drug therapies to prevent the spread of cancer. We have found that LIMK1 is very important in controlling the polymerisation of one of the most abundant molecules in the cell, actin. We have now preliminary data to show that LIMK1 also controls another important cellular protein, tubulin. Changes in tubulin polymerisation are of extreme importance for cell division and drugs affecting the state of tubulin are very potent as anti-cancer drugs. The goals of this research are: (1) To confirm that LIMK1 regulates the polymerisation of tubulin and (2) To demonstrate that LIMK1 regulates tubulin polymerisation by controlling the activity of p25, a protein involved in tubulin polymerisation that is modified by LIMK1. The results from this research will be highly significant because LIMK1 is a novel drug development target. Drugs that inhibit this protein may block the ability of tumours to invade and metastasise. Therefore, we have to identify the other functions of LIMK1 to eliminate the possibility that drugs that inhibit LIMK1 and metastasis don't affect other organs and cells in the body. New molecules regulated by LIMK1 may also be suitable targets for drug development because through their inhibition we may also regulate other LIMK1 activities and possibly metastasis.Read moreRead less
A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth ....A major feature of tumour progression and cardiac hypertrophy (enlarged heart) is accelerated cell growth and protein synthesis. Moreover, increased synthesis of ribosomes (the protein synthetic machinery) is associated with malignancy and hypertrophy suggesting that it may play a causal role in tumour formation and cardiac disease. In support of this, specific inhibitors of both ribosome biogenesis and function are extremely effective at inhibiting the growth of some tumours and vascular smooth muscle. This study will examine the mechanisms that regulate ribosome synthesis. Specifically it focuses on a transcription factor termed UBF whose activity we think is critical for the regulation of the synthesis of the ribosomal RNA, the catalytic backbone of the ribosomes. Understanding the molecular mechanism(s) controlling UBF function will lead to a better comprehension of how cells modulate synthesis of functional ribosomes and how this process is deregulated during disease states associated with deregulated protein synthesis and growth such as cardiac hypertrophy and cancer.Read moreRead less
Tyrosine Kinases And Phosphatases In Cell Cycle Checkpoint Responses
Funder
National Health and Medical Research Council
Funding Amount
$513,946.00
Summary
In order for an organism to grow and develop, the cells that make up the tissues and organs need to undergo a process of cellular division, wherein individual cells grow and then divide into two cells. During this process of cellular growth and division the entire genome needs to be duplicated (this occurs during S-phase) and then divided equally into the two daughter cells. In S-phase several so-called 'checkpoint' mechanisms exist which ensure that this occurs in an orderly and precise manner. ....In order for an organism to grow and develop, the cells that make up the tissues and organs need to undergo a process of cellular division, wherein individual cells grow and then divide into two cells. During this process of cellular growth and division the entire genome needs to be duplicated (this occurs during S-phase) and then divided equally into the two daughter cells. In S-phase several so-called 'checkpoint' mechanisms exist which ensure that this occurs in an orderly and precise manner. The so-called 'DNA replication checkpoint' delays S-phase progression in response to 'replication stresses' that may otherwise cause DNA damage. Protein tyrosine kinases (PTKs) are hyperactivated in many human solid tumours and blood malignancies contributing to varied aspects of tumour progression. Our preliminary studies indicate that the inactivation of PTKs by protein tyrosine phosphatases may be essential for the suppression of S-phase progression in response to replication stress. Our goal is to understand the molecular mechanisms by which PTKs and tyrosine phosphatases contribute to S-phase checkpoints. Our studies will provide important insights into DNA replication stress-induced checkpoint responses in mammals and identify unprecedented mechanisms by which hyperactivated PTKs may contribute to tumour development.Read moreRead less