Investigation Of Steroidogenesis As A Mechanism Of Castration Resistance In Human Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$419,076.00
Summary
Prostate cancer is critically dependent upon continued testosterone stimulation, even when the disease becomes resistant to existing hormonal therapies that suppress serum levels. The source of this testosterone is currently unclear. This study aims to identify the site of testosterone synthesis in patients with prostate cancer, and determine the relevance of continued testosterone signalling in patients treated with 'super castrating' hormonal therapy.
Estrogen Therapy For Castrate Resistant Prostate Cancer
Funder
National Health and Medical Research Council
Funding Amount
$531,690.00
Summary
Withdrawal of male hormones in men with prostate cancer is effective therapeutically because it causes cell death in most of the tumour. However the remaining cells (called castrate resistant cells), give rise to recurrent disease that inevitably kills the patient. This project aims to test if our compound will kill these cells and prevent recurrence or if it has any benefit for the patients who have incurable disease.
Dissection Of The Mechanisms Of Action Of Evolutionarily Conserved Apoptotic Pathway Components
Funder
National Health and Medical Research Council
Funding Amount
$253,500.00
Summary
Animals eliminate unwanted cells through a highly controlled process termed apoptosis. Defects in apoptosis can contribute to cancer or autoimmune disease. Conversely, diseases such as stroke and Alzheimer's disease have been linked to excessive cell death. To develop drugs that promote apoptosis when it fails to occur, or prevent inappropriate cell death, it is necessary to elucidate the molecular mechanisms controlling apoptosis. The first recognised component of the mammalian cell death machi ....Animals eliminate unwanted cells through a highly controlled process termed apoptosis. Defects in apoptosis can contribute to cancer or autoimmune disease. Conversely, diseases such as stroke and Alzheimer's disease have been linked to excessive cell death. To develop drugs that promote apoptosis when it fails to occur, or prevent inappropriate cell death, it is necessary to elucidate the molecular mechanisms controlling apoptosis. The first recognised component of the mammalian cell death machinery was Bcl-2; a protein associated with development of cancer. Despite much research since then, the way in which Bcl-2 and related proteins function is still unknown. This project capitalises on previous genetic and biochemical studies in a model genetic organism (the roundworm) to address this important issue. Animal cell death pathway components can be introduced into yeast such that activation of the introduced pathways leads to yeast death and its inhibition promotes yeast survival. We have used this approach to reconstitute the worm cell death pathway and a major mammalian apoptosis pathway in yeast. Yeast strains bearing these reconstituted pathways will be used to test functional equivalence of candidate mammalian proteins and their putative roundworm counterparts. The system will also be exploited to identify and characterise novel proteins that regulate cell death in mammals and worms. Understanding the way in which key molecules regulate apoptosis will assist in the development of diagnostic and therapeutic reagents for many diseases in which cell death regulation is perturbed. This project capitalises on the evolutionary conservation of apoptosis to characterise the mechanisms of action of important mammalian apoptotic regulators and to seek novel mammalian apoptotic pathway components. Proteins identified in this way are likely to be important apoptotic regulators, as our approach ensures that their functions are evolutionarily conserved.Read moreRead less
Role Of Zinc In The Respiratory Epithelium And Asthma
Funder
National Health and Medical Research Council
Funding Amount
$224,250.00
Summary
This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example ....This project will use a panel of Zinquin-derived Zn fluorophores developed in our laboratory, as well as probes for the mammalian family of vesicular ZnT transporters, to carry out a study of the normal physiology of Zn in the respiratory system and potential abnormalities of this in patients with chronic inflammatory respiratory disease (asthma, COPD, chronic smoking). Chronic inflammatory diseases of the respiratory tract affect a significant proportion of the Australian community. For example, asthma affects 12% of adults and amongst these, 15% waken weekly or more often with their asthma while 6% are hospitalized annually. There is a need to understand the basic mechanisms underlying these diseases so that new strategies can be developed to modify bronchocondtriction and inflammation. The project will provide new knowledge concerning the physiology of Zn in the respiratory epithelium and interactions between Zn deficiency and oxidants on injury in the respiratory tract. The usefulness of easily accessible nasal epithelial cells as a measure of Zn and Zn transporter levels deeper in the respiratory tract will be assessed. The project encompasses a number of fields and utilizes in vitro cellular and animal models, as well as tissues from human subjects.Read moreRead less
REGULATION OF ANDROGEN RECEPTOR And ErbB-2 GENE EXPRESSION IN PROSTATE CANCER: ROLE OF THE HU PROTEINS
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
Carcinoma of the prostate (PCa) is the most common malignancy affecting males and causes enormous morbidity and mortality in Australia. It is the second leading cause of death in men in Western countries. About one third of men relapse after radical prostatectomy because of previously undetectable metastatic disease. Androgens, acting via the androgen receptor (AR) a nuclear transcription factor that regulates a set of largely unknown androgen-responsive genes, promote the growth of prostate can ....Carcinoma of the prostate (PCa) is the most common malignancy affecting males and causes enormous morbidity and mortality in Australia. It is the second leading cause of death in men in Western countries. About one third of men relapse after radical prostatectomy because of previously undetectable metastatic disease. Androgens, acting via the androgen receptor (AR) a nuclear transcription factor that regulates a set of largely unknown androgen-responsive genes, promote the growth of prostate cancer cells. Thus the AR is a major target for therapy. Even when the disease is unresponsive to androgen withdrawal, the AR is present. Furthermore, we know that these PCa cells recruit other androgen-independent pathways to activate growth. One such pathway is the erbB-2 signaling cascade, which drives the cells towards proliferation. Proteins that bind to RNA, the cellular messenger, are playing an increasing role in the biology of cancer. HuR, a member of the Hu-Elav family, augments growth of colon cancer cells, and is associted with poor outcomes in ovarian and brain malignancies. We have recently identified the first proteins that bind to AR and erbB-2 mRNA. Remarkably, HuR binds to both sequences. Furthermore, HuD, another member of the Hu-Elav family which is normally only found in the brain, is aberrantly expressed in human PCa. In this Project we will determine the effects of these proteins on the growth of human PCa cells in culture and in whole animal models. We will also evaluate their presence in a large array of human PCa specimens. It is envisaged that this work will develop novel links between the two pathways bringing them together in a previously unrecognised manner. We also aim to solve the molecular structure of Hu proteins bound to the AR mRNA. Outcomes of the work will include new potential tests for prostate cancer and improved prognosis prediction, and establishment of a foundation for the development of novel targets for therapy.Read moreRead less
Temporal And Spatial Regulation Of Caspases In Development And Metamorphosis
Funder
National Health and Medical Research Council
Funding Amount
$369,072.00
Summary
Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in g ....Cell death by a special process called apoptosis is a means of deleting unwanted and harmful cells from the body. Extensive apoptosis occurs during foetal development which is required to get rid of many excess cells produced during the growth of the embryo. Selective apoptosis is also essential for the formation of different tissues and organs in developing foetus. In the adult, apoptosis is required for proper functioning of the immune system, to remove virus infected and cancer cells and in general to maintain the correct number of cells in the body. As such, dysregulation of apoptosis is associated with the pathogenesis of a wide array of diseases such as autoimmune diseases, many forms of cancer and neurodegenerative disorders (such as Alzheimer's and Parkinson's diseases), heart disease, ischaemia and other conditions. To understand, manage and treat disorders that result from aberrant apoptosis, we need to know at molecular and cellular level, how apoptosis is brought about and how it is regulated. We have been studying these processes in detail for several years. Central to the apoptotic execution of cell death are a group of proteases that target many cellular proteins for specific cleavage. The activation of these proteases is the crucial step in the initiation of apoptosis and therefore each cell has developed complex ways to control this process. If we understand how these regulatory mechanisms operate, we can then formulate strategies that are targeted towards pathologies involving abnormal apoptosis. Various molecules that are involved in the execution and regulation of apoptosis are potentially excellent targets for therapeutic intervention in a number of disorders and will lead to the development of novel drugs for the treatment and prevention of many pathological conditions. In the present proposal, we aim to study what type of caspases are involved in sculpting of various organs and tissues during development.Read moreRead less