Blimp-1: A Master Regulator Of B-lymphocyte Terminal Differentiation?
Funder
National Health and Medical Research Council
Funding Amount
$154,250.00
Summary
B lymphocytes are the antibody-producing cells of the immune system. They are formed in the bone marrow, and are exported to the body to circulate, searching for signs of infection. These circulating cells are not fully mature, but when they encounter an invader, with the help of other immune cells, they change. Most become antibody-producing cells, the final, operational cells of the B cell lineage. A few cells are set aside as memory cells that can rapidly become antibody-producing cells shoul ....B lymphocytes are the antibody-producing cells of the immune system. They are formed in the bone marrow, and are exported to the body to circulate, searching for signs of infection. These circulating cells are not fully mature, but when they encounter an invader, with the help of other immune cells, they change. Most become antibody-producing cells, the final, operational cells of the B cell lineage. A few cells are set aside as memory cells that can rapidly become antibody-producing cells should the same infection occur again. This is the basis of vaccination. The secretion of antibodies into the serum (that can bind to and eliminate an invader anywhere in the body) is the main function of B lymphocytes. This project will study the genes that allow B cells to become antibody-secreting cells (called ASC). We will focus on the gene for Blimp-1, the B lymphocyte-induced maturation protein, which has been called the master regulator of ASC formation. This claim is based largely on circumstantial evidence, and has not been directly tested genetically. We have made a mouse in which the Blimp-1 gene has been altered so that we can disable it in carefully controlled way. Using this knockout mouse, we can directly test the requirement for Blimp-1 in ASC and in other cell types. We will study these animals, using many tests that can accurately measure the behaviour of isolated cells, or the immune responses of the animals. We will examine other genes that are thought to be required for ASC to form or to perform their work, to see if loss of Blimp-1 (a known gene silencer) has impacted on these other genes. In this way, we expect to identify the genetic program that drives a B cell to become a mature ASC. Using this knowledge, we hope eventually to be able to study diseases of ASC in humans (as occur in allergy, asthma, rheumatoid arthritis and leukaemia). This information may also be used to improve the outcome of vaccination.Read moreRead less
Promoting Intestinal Stem-cell Mediated Regeneration Following Damage: A Critical Role For Neuregulin 1
Funder
National Health and Medical Research Council
Funding Amount
$648,447.00
Summary
Diseases, infections and pathologies are common clinical problems of the intestine in humans that can lead to loss of intestinal tissue. Individuals with these conditions can experience nutritional problems and severe cases result in death. Promoting regeneration of the damaged tissue is critical to re-establish intestinal function. In this study, we will examine the regenerative potential of a growth factor called Neuregulin1 in the intestine with the aim of facilitating tissue regeneration.
The Role Of Raptor And Rictor Signalling Pathways In Osteogenesis And Mesenchymal Stem Cell Fate Determination
Funder
National Health and Medical Research Council
Funding Amount
$562,742.00
Summary
Skeletal diseases associated with excessive bone loss and skeletal fragility, such as osteoporosis, affect 2.2 million Australians and cost our health system approximately $7.4 billion per annum. Studies from our laboratory suggest a critical role for the mTOR signalling pathway in bone development. Using transgenic animals and state-of-the-art techniques, we will investigate the role of mTOR in pre- and post-natal skeletal development. Results from these studies may provide novel approaches to ....Skeletal diseases associated with excessive bone loss and skeletal fragility, such as osteoporosis, affect 2.2 million Australians and cost our health system approximately $7.4 billion per annum. Studies from our laboratory suggest a critical role for the mTOR signalling pathway in bone development. Using transgenic animals and state-of-the-art techniques, we will investigate the role of mTOR in pre- and post-natal skeletal development. Results from these studies may provide novel approaches to treat age-related bone loss syndromes.Read moreRead less
De-differentiation Of Committed Cells Into Haematopoietic Stem Cells By The Instructive Role Of The Transcription Factor HOXB4
Funder
National Health and Medical Research Council
Funding Amount
$683,040.00
Summary
Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem ....Blood stem cells are long-lived and can give rise to every cell type of the blood system and due to these properties they are currently used in the clinics. Despite their importance, our knowledge of the mechanisms the control the multiplication of these rare cells is very scarce. This proposal aims to identify key factors that have the potential to convert mature, easy available blood cells into stem cells. This knowledge has to potential to lead to novel system that allow the expansion of stem cells for transplantations in the future.Read moreRead less
Investigating The Formation And Utility Of The Prenatal Platelet Forming System
Funder
National Health and Medical Research Council
Funding Amount
$793,442.00
Summary
A major challenge to regenerative medicine is discovering how to produce useful cell types in the laboratory. Particularly urgent is the need to generate large numbers of platelets, the building blocks of the clotting system, for clinical use. Current laboratory methods are woefully inefficient, thus cannot meet demand. This project aims to discover how platelets are made in nature. With this information we will be able to devise better platelet production strategies in the laboratory.
A Stem Cell-specific MicroRNA-independent Function Of Drosha
Funder
National Health and Medical Research Council
Funding Amount
$637,702.00
Summary
Stem cells are responsible for producing and replenishing the ~200 specialised cell types in our body. Our goal is to understand the molecular switches that control the function of these cells. We recently discovered that the activity of certain genes within stem cells is controlled by degradation. This degradation is absolutely crucial for safeguarding the function of stem cells. This project will investigate how this novel mechanism is controlled within these cells.
The Regulation Of Pluripotency And Self-renewal In Embryonic And Germline Stem Cells.
Funder
National Health and Medical Research Council
Funding Amount
$491,767.00
Summary
Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell based therapies promises to revolutionize the treatment of many common human diseases. For instance, in neurodegenerative conditions such as Parkinsons disease, normal ....Regulation of self-renewal and developmental potential in embryonic and germline stem cells. The capacity of some stem cells to self-renew and under specific conditions, give rise to all adult cell types, a property known as pluripotency , is the key to unlocking the potential of cell based therapies. The development of stem cell based therapies promises to revolutionize the treatment of many common human diseases. For instance, in neurodegenerative conditions such as Parkinsons disease, normal embryonic stem cells grown in culture could be used to replace the lost or disabled neurons in the patient. Many other conditions including diabetes, cystic fibrosis, myocardial infarction (heart attack) and stroke could potentially be treated with stem cell based therapies. Understanding the molecular regulators that govern establishment and maintenance in culture of stem cell lines derived from embryos and from germ cells is the primary goal of this study. We will use well-established techniques to genetically manipulate mouse embryonic stem cells and embryos to examine the role of a specific gene, NANOG. Named after the Celtic legend of Tir NaNog (land of the ever young). When NANOG was forced to remain active, embryonic stem cells were able to grow in media deficient in factors usually required for self-renewal and did not lose their pluripotency even when treated with chemical agents that usually induce differentiation. Understanding the full capacity of NANOG to influence stem cell self-renewal and elucidation of the underlying molecular pathways regulated by this gene will provide valuable insights into the establishment and manipulation of stem cell lines from embryonic and adult tissues.Read moreRead less
Understanding The Ancestry Of De Novo Blood Formation In The Early Embryo
Funder
National Health and Medical Research Council
Funding Amount
$484,666.00
Summary
Current laboratory methods rely on a hit-or-miss approach for the production of such cells, making the prospect of producing patient-specific cells an inefficient/financially prohibitive process. This project aims to generate new knowledge into when and how fate of early blood cells in selected in nature. With this information we will be able to devise effective blood progenitor cell production strategies in the laboratory.