Genetic Analysis Of Cell Death Pathways, Drug Resistance And Oncogenic Co-operativity In IL-3 Dependent Cell Lines
Funder
National Health and Medical Research Council
Funding Amount
$445,270.00
Summary
The ultimate fate of most of our cells is to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . Inappropriate apoptosis can contribute to cell loss following heart attacks, stroke or neurodegenerative diseases, such as Alzheimer s or Parkinson s disease. Conversely, when cell death fails to occur, abnormal cells can accumulate and lead to cancer. In addition, because drugs ....The ultimate fate of most of our cells is to die by committing suicide, because they are no longer required, are no longer functioning, or are potentially harmful. This normal physiological process is termed apoptosis . Inappropriate apoptosis can contribute to cell loss following heart attacks, stroke or neurodegenerative diseases, such as Alzheimer s or Parkinson s disease. Conversely, when cell death fails to occur, abnormal cells can accumulate and lead to cancer. In addition, because drugs that are used to treat cancer may exert their effect by inducing apoptosis, a failure of this suicide response may cause resistance to chemotherapy. The genes of the apoptosis pathway function either to promote or inhibit cell death. We have found that some genes in the apoptosis pathway allow apoptosis to proceed rapidly, but do not decide the fate of the cell. Other genes are required for a cell to commit to die. If these genes are mutated then apoptosis does not occur and a functional cell may survive. The distinction between cells that decide fate and those that do not is crucial because it is only the genes that decide cell fate that can act as cancer genes, and are valid targets for therapy. We use a model in which apoptosis is caused by removal of a growth factor, using cell lines derived from mice that lack particular genes in the cell death pathway. These cells proliferate normally in the presence of growth factor, and allow us to determine the role of the genes when growth factor is withdrawn. Because these cells are sensitive to chemotherapeutic drugs, we can also determine the contribution these genes make to cancer drug sensitivity. Using this system, we have discovered that Puma, a gene known to be required for apoptosis in response to radiation, is also a critical activator of apoptosis following growth factor withdrawal. We will determine the manner in which Puma is regulated by growth factors, as well as identify and characterise other key components.Read moreRead less
Immunological Studies Of Adjutant Induced Arthritis
Funder
National Health and Medical Research Council
Funding Amount
$412,104.00
Summary
This project stems from our interest in rheumatoid arthritis and a number of other forms of arthritis that affect many joints in a symmetrical fashion (the polyarthritides). In most instances, there is evidence that the diseases are caused by an attack on the joint lining (the synovium) by cells of the immune system. Rheumatoid arthriis is the most common and often the most severe of the polyarthritides. Neither the triggering event nor the target of the attack by the immune system is understood ....This project stems from our interest in rheumatoid arthritis and a number of other forms of arthritis that affect many joints in a symmetrical fashion (the polyarthritides). In most instances, there is evidence that the diseases are caused by an attack on the joint lining (the synovium) by cells of the immune system. Rheumatoid arthriis is the most common and often the most severe of the polyarthritides. Neither the triggering event nor the target of the attack by the immune system is understood and as a result, there are no specific preventative measures against the disease or specific therapies for the established disease. There is, however, strong evidence that the cells involved in the attack on the synovium are orchestrated by a white blood cell called the T lymphocyte. T lymphocytes cannot operate alone but require a second cell, the dendritic cell, to present the target in a special way which can be recognised and responded to by the T lymphocyte. The T cell and the dendritic cell are the two central aspects of this project. We will use an animal model of polyarthritis to allow access to these cells during the earliest phases of the disease, a silent period not recognisable in the earliest stages of rheumatoid arthritis. T lymphocytes from animals with experimental polyarthritis will be used as indicators in the search for the target of the disease process and dendritic cells from affected joints will be used as a natural source of that target. By the production of highly specific T lymphocytes (members of clones), we hope to identify the target molecules of the disease process. This information should lead ultimately to the identification of the triggering stimulus (and thence prevention) and to the development of highly specific therapies designed to treat the established disease.Read moreRead less
Local Microvascular Regulatory Mechanisms In Diabetes: Relevance To Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore norma ....In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore normal metabolism, leaving patients at risk of developing complications involving the circulatory and nervous systems. An understanding of the processes involved in the development of such complications would allow alternate treatment strategies to be devised in order to improve the quality of life and life expectancy of diabetic patients. The events leading to abnormalities in the function of the circulatory and nervous systems are uncertain, however, studies have demonstrated that in diabetes there may be an insufficient blood supply to nerves and this would be expected to cause nerve damage. At present, our understanding of the factors involved in regulating blood flow to nerves is limited. The studies described in this proposal are aimed at testing the hypothesis that nerve blood vessels are themselves involved in the regulation of flow through an intrinsic ability to change their diameter in response to tissue demands and that in diabetes alterations in the capacity of nerve blood vessels to constrict or dilate compromises their role in the control of nerve blood flow . Information obtained from these studies will improve our understanding of the early disturbances in the function of circulatory and nervous systems leading to alterations in blood flow which precede the development of overt changes characteristic of the complications associated with diabetes. This will provide insight into developing new treatment strategies for diabetic patients.Read moreRead less
The Role Of Oxidative Stress In The Patho-aetiology Of Prion Disorders Using Infected Cell Culture And Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$112,014.00
Summary
The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this gr ....The transmissible spongiform encephalopathies (TSE; also known as prion diseases) are a biologically unique and fascinating group of invariably fatal diseases which primarily affect the brains of both humans and animals. In humans, sporadic Creutzfeldt-Jakob disease (CJD) is the most common form, while in animals it is the recent epidemic of bovine spongiform encephalopathy (mad cow disease), and its probable transmission to humans as new variant CJD, which has drawn so much attention to this group of disorders. The preponderance of scientific evidence now supports the belief that infectivity in TSEs relates predominantly (probably exclusively) to a protein (called the prion protein; PrP) which is normally found on the cell surface of a number of types of brain cells, including neurons. Transmissibility, and hence infectivity, is more correctly associated with a malfolded version of PrP into an abnormal shape which gives the mutant protein significantly different biological and biochemical properties, including relative resistance to breakdown by enzymes that metabolise proteins (proteases) and enhanced tendency to aggregate. However, the precise steps involved in this transformation to the abnormal infectious form of PrP are not known. Similarly, our understanding of how different folding and accumulation of this protein brings about disease is not clear. Nevertheless, as with other neurological diseases (eg Alzheimer's disease) which are a consequence of unexplained spontaneous premature degeneration of parts of the brain (neurodegenerative diseases), oxidative stress is increasingly believed to play a role. Oxidative stress is a generic term used to describe the enhanced production within a cell of small, very harmful, oxygen containing molecules which under normal circumstances can be successfully detoxified. This project involves a detailed study of the role of oxidative stress in the causation of prion diseases using both mouse and cell culture models.Read moreRead less