Does CD123 Provide A Biological Advantage To Leukaemia Stem Cells?
Funder
National Health and Medical Research Council
Funding Amount
$647,637.00
Summary
Leukaemia is a devastating form of blood cancer affecting both young and old. We need to understand the diseased stem cell to eradicate this disease. Current therapy is poorly tolerated and the majority of patients ultimately die at relapse. We intend to investigate how we can make the cells more susceptible to therapy by understanding their biology.
Autocrine Vitamin D Metabolism, Activity And Bone Health
Funder
National Health and Medical Research Council
Funding Amount
$459,270.00
Summary
This project will provide the detailed understanding of the activities of vitamin D within the bone microenvironment and offers the exciting prospect of elucidating the mechanistic reasons for maintaining an adequate vitamin D status in relation to the prevention of osteoporotic hip fractures. Thus, this project has great potential to improve community health by being able to recommend vitamin D supplementation made on the basis of maintaining normal bone cell function.
A Newly Identified Role For 14-3-3zeta Protein In Thrombosis And Platelet Procoagulant Activity
Funder
National Health and Medical Research Council
Funding Amount
$556,327.00
Summary
Cardiovascular disease, including heart attack and stroke is the major cause of death globally, and is responsible for the death of 50,000 Australians each year. Platelet activation and blood coagulation play an important role in these diseases and we have discovered that a protein called 14-3-3 zeta is important in the processes that result in thrombosis. We are studying the mechanisms by which this protein contributes to life-threatening platelet activation with the aim of developing new and m ....Cardiovascular disease, including heart attack and stroke is the major cause of death globally, and is responsible for the death of 50,000 Australians each year. Platelet activation and blood coagulation play an important role in these diseases and we have discovered that a protein called 14-3-3 zeta is important in the processes that result in thrombosis. We are studying the mechanisms by which this protein contributes to life-threatening platelet activation with the aim of developing new and more effective anti-thrombotic drugs.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
Hormonal Control Of Serotli Cell Maturation And Function
Funder
National Health and Medical Research Council
Funding Amount
$512,898.00
Summary
This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR ac ....This project will determine the key roles of androgen in the Sertoli cell, a unique highly specialised cell that provides essential nutritional and structural support for sperm production. Androgen acts via the androgen receptor (AR), which is vital for initiating and maintaining sperm development. In current NHMRC-funded research we successfully established new mouse models designed to study AR, in particular its regulation of gene expression, in the Sertoli cell. We revealed that genomic AR activity within Sertoli cells is essential for 'induction' of complete sperm development. Ongoing work will develop unique 'inducible' transgenic models that will allow, for the first time, selective analysis of Sertoli AR in both 'developing' and 'adult' testes. Our innovative models will allow AR function to be switched on or off at any stage of development, providing unique opportunity to determine the key AR-regulated factors and pathways controlling induction, maintenance or restoration of sperm production. In past NHMRC research we created a novel transgenic model to study another major reproductive hormone, FSH. Using the hormone-deficient background of 'hpg' mice, we found that androgen and FSH act synergistically in the developing 'meiotic' germ cells that form sperm. Using the latest microarray gene technology we generated datasets of androgen-regulated genes with or without FSH activity, which combined with our unique transgenic AR and FSH models, will be used to identify key pathways, including those enhanced by androgen-FSH synergism, in the early testicular response. Our research will provide new knowledge of the precise roles and pathways of testicular AR actions, to ultimately identify key genetic and regulatory factors as targets for significantly improved therapy for male infertility, gonadal tumours, or contraception.Read moreRead less
Development Of Anti-CXCR7 MAbs For The Treatment Of Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$399,998.00
Summary
Fibrosis is a serious biological process that occurs in many disease conditions, including cancer, inflammation and infections. We have produced antibodies to CXCR7, and these antibodies completely inhibit fibrosis in a mouse model. We plan to develop these antibodies in to a suitable drug for human clinical trials.
Validation Of Stat3 As A Therapeutic Target In Diseases Arising From Its Inappropriate Activation By Gp130 Cytokines
Funder
National Health and Medical Research Council
Funding Amount
$674,142.00
Summary
Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the exte ....Stomach cancer is the third most prevalent cancer in the Western World and result in the yearly death of several thousand people in Australia alone. We have discovered a specifice gene mutation of a receptor molecule called gp130 that results in the formation of stomach cancer in mice. We are now aiming to understand the exact molecular events by which this mutation results in the uncontrolled growth of stomach lining cells. We will employ a number of strategies to establish molecularly the extent to which this mouse model is informative for gastric cancer inhuman. In aprticular we will identify the genes that are involved in the progression of the disease. One important focus of the project is to see whether or not the moelcule (called Stat3) whose aberrant activation triggers the disease in the mouse could provide a future pharmacological target for intervention with the disease. Similarly with expertise of CIB, we will investigate with novel proteomics techniques whther we can identify a protein in the serum of these mice, which could give us aclue of whether or not the mouse ahs already developed disease. Such a protein could be of potentail diagnostic importance in the future to screen human for gastric cancer which in its eraly stages is usually without any clinical symptoms. In a related Aim we will find out the gene that can genetically cooperate with Stat3 and that is required to enable survival of newborn mice. It may well turn out mOur proposal combines the expertise of the two investigators in signal transduction and that this gene may be an important determinant to ensure that Stat3 triggers physiological rather than pathological responses in many differnet organs.Read moreRead less
Appendicitis, Protection Again Colitis And The Role Of Colonic Regulatory T Cells
Funder
National Health and Medical Research Council
Funding Amount
$67,381.00
Summary
The appendix has been regarded as a useless organ, however, there are evidence showing its removal reduces the risk of developing inflammatory bowel disease. We have shown that this may be due to altered intestinal immune regulation. The project plans to explore the mechanisms responsible for this altered immune regulation. With knowledge of specific elements of disease causation gained from these studies, more effective and targeted treatment options will become available.
Characterisation Of The Adiponectin Receptors - AdipoR1 And AdipoR2
Funder
National Health and Medical Research Council
Funding Amount
$445,158.00
Summary
The increasing incidence of cardiometabolic disease highlights an unmet need for novel therapeutic approaches. Greater understanding of the detail governing cardiometabolic function is required to provide a foundation to construct effective strategies. We will characterise 2 novel receptors that are important in the regulation and maintenance of cardiometabolic systems, seeking to identify strategies to enhance receptor, improve cardiometabolic function and reduce disease burden.