This project concerns the basic biology of large white blood cells called macrophages. Macrophages are required for the immediate defence against infection, wound repair and normal turnover of tissues, but they can also produce toxic products that cause illness, especially in inflammatory diseases and cancer. We are studying a gene that is normally only produced in macrophages, but appears abnormally in many cancer cells. Our aim is to understand at a molecular level exactly how the gene is cont ....This project concerns the basic biology of large white blood cells called macrophages. Macrophages are required for the immediate defence against infection, wound repair and normal turnover of tissues, but they can also produce toxic products that cause illness, especially in inflammatory diseases and cancer. We are studying a gene that is normally only produced in macrophages, but appears abnormally in many cancer cells. Our aim is to understand at a molecular level exactly how the gene is controlled, and why it appears in tumours.Read moreRead less
Many people with organ failure such as heart or kidney disease need a transplant to survive. In the case of kidney failure patients can be kept alive by the artificial kidney however this sort of mechanical traeatment is much less satisfactory than a transplant. Unfortunately most patients who would benefit from a transplant are unable to receive one beacuse of the shortage of living or cadaver donors. A possible solution to this shortage of organs for transplantation is to use animal organs. Pi ....Many people with organ failure such as heart or kidney disease need a transplant to survive. In the case of kidney failure patients can be kept alive by the artificial kidney however this sort of mechanical traeatment is much less satisfactory than a transplant. Unfortunately most patients who would benefit from a transplant are unable to receive one beacuse of the shortage of living or cadaver donors. A possible solution to this shortage of organs for transplantation is to use animal organs. Pigs are the most suitable animal donor. However, a pig-to-human organ is rejected immediatly because of the distance between the species. Over the last 10 years, we and others have been trying to understand which genetic differences are important. It is now clear that there are several important differences. One of these is a Blood Group like molecule in the pig that humans react with immediatly on transplantation. This is called the Gal molecule. We and others have been successful in removing the pig gene that makes this molecule. In addition we have added several human genes to pigs to prevent the early vigorous rejection which usually occurs. Organs from these genetically modified pigs have been tested by transplantation into baboons and monkeys. The transplants which used to be rejected within minutes, now survive for months. However, they organs are still rejected by a process which causes clotting in the transplanted organs. We now understand the mechanism andare making genetically modified pigs with human genes which regulate clotting of human blood. This project will test organs from these pigs by transplantation into baboons. We will also make a special strain of pigs in which all these genetic modifications are assembled. This involves the removal of one pig gene and the addition of 4 or 5 human genes. We think it is highly likely that this combination of genetic modifications will make this strain of pigs much more suitable as organ donors.Read moreRead less
Identification Of Critical Regulatory Elements In The BRCA1 Gene
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the molecular defects that contribute to disease initiation and progression. Over the last twenty years significant progress has been made in this regard, however there still remain a considerable number of unanswered questions. For example, it is not yet clear precisely what contribution each of the ....Breast cancer affects approximately one in ten women and is therefore a major health problem. In order to improve the diagnosis, treatment and prognosis of this disease, it is critical to understand the molecular defects that contribute to disease initiation and progression. Over the last twenty years significant progress has been made in this regard, however there still remain a considerable number of unanswered questions. For example, it is not yet clear precisely what contribution each of these genes makes. This is largely due to limitations in current mutation detection strategies and an incomplete understanding of all of the genetic elements for which disruption can lead to loss of gene function. This propsal aims to identify all of the genetic elements critical for the expression of an important breast cancer gene called BRCA1. Furthermore, it aims to determine the status of these elements in breast cancer patients, thus expanding our knowledge of the actual contribution disruption of this gene makes to this disease.Read moreRead less
Characterization Of The FHL Protein Family In Striated Muscle
Funder
National Health and Medical Research Council
Funding Amount
$500,750.00
Summary
This grant examines the role of a family of muscle proteins, called FHL proteins, in skeletal and heart muscle. Inherited muscular disorders such as muscular dystrophy and myopathies, cause muscle weakness, which may be profound and lead to premature death due to respiratory muscle failure, or cause mild weakness later in life. The proteins which are defective in these muscular dystrophies are structural muscle proteins, which link and stabilize the contractile fibres in muscle and protect the m ....This grant examines the role of a family of muscle proteins, called FHL proteins, in skeletal and heart muscle. Inherited muscular disorders such as muscular dystrophy and myopathies, cause muscle weakness, which may be profound and lead to premature death due to respiratory muscle failure, or cause mild weakness later in life. The proteins which are defective in these muscular dystrophies are structural muscle proteins, which link and stabilize the contractile fibres in muscle and protect the muscle from the stresses and damage resulting from repeated muscular contraction. We have identified that the FHL proteins, which are the focus of this grant application, bind to and potentially regulate muscle proteins, which have been shown to cause forms of muscular dystrophy and cardiomyopathy. Examination of these interactions will provide insights into the biological mechanism of these muscle disorders. Furthermore, one of these proteins, FHL1 is significantly increased in hypertrophic cardiomyopathy, heart muscle thickening, a major cause of sudden cardiac death in young adults. We are creating transgenic mice, which make increased levels of FHL1 protein in their heart muscle, to determine whether increased FHL1, by itself is sufficient to promote heart muscle thickening. These studies should lead to further understanding of the development of diseases of heart and skeletal muscle, which may lead to novel treatments in the future.Read moreRead less
Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone ....Hormones are essential chemical messengers that regulate the normal functions of the body. Reproduction in particular is widely influenced by hormones. The development of the very early embryo and its implantation into the uterus is not well understood. A new class of hormone has been implicated in this process. This hormone, known as platelet-activating factor (or PAF) is special among hormones since it belongs to a class of chemicals known as phospholipids. This is quite uncommon. This hormone can act in an apparently contradictory fashion. Its production by the embryo allows it to act back on the embryo to stimulate embryo growth and survival. The embryo (of some species) then releases other hormones which prevents the PAF from acting on the uterus. If this repression of the uterine response to PAF does not occur then PAF acts on the uterus to stop further progression of the pregnancy (luteolysis). Hormones act on cells via special cell proteins known as receptors. It seems that the receptor for PAF in the embryo and the uterus are different and may therefore result in triggering different cellular responses by these 2 tissues. We have available to us mice with mutations that stop the functioning of these two likely classes of receptors. The progress of pregnancy and the development of embryos in mice with these mutations will be studied as a means of defining how PAF acts in pregnancy. The embryo will be studied in detail to determine the nature of the changes induced within the embryo by PAF acting via its receptor. One of these receptors is an entirely new class of molecules not previously understood to be able to act as a cell signalling devise. This study will describe if and how this potential new receptor acts in the embryo, allowing future detailed investigation of its role in normal cell function. It will show how this single hormone can regulate both the uterus and embryo to have contradictory roles in the establishment of pregnancy.Read moreRead less