Characterisation Of Novel Regulators Of The Haemopoeitic System.
Funder
National Health and Medical Research Council
Funding Amount
$381,680.00
Summary
All of the circulating blood cells (including red cells and white cells) develop from a single cell type, called the haemopoietic stem cell (HSC), found in the adult bone marrow. Normally, HSCs are gradually restricted to become only one cell type and once they have started down that pathway can no longer generate cells of another pathway (e.g. once HSC begin to develop into red blood cells, they cannot normally change their direction to become white cells). There are a few examples of mature ce ....All of the circulating blood cells (including red cells and white cells) develop from a single cell type, called the haemopoietic stem cell (HSC), found in the adult bone marrow. Normally, HSCs are gradually restricted to become only one cell type and once they have started down that pathway can no longer generate cells of another pathway (e.g. once HSC begin to develop into red blood cells, they cannot normally change their direction to become white cells). There are a few examples of mature cells, however, that have changed pathways. We have use one of these, the mouse J2E red cell changing into macrophages, to identify the genes involved in this process. Two of the genes we found, HLS5 and HLS7, are potentially important in lineage determination and normal blood development as well as the formation of blood cancers. This project aims to investigate the roles these genes play in blood development. Much of our work to date has focused on HLS7. The human equivalent of HLS7 was found by an American group independently of us as a gene which causes one type of blood cancer. We have shown HLS7 has dramatic effects on normal blood development and, together, these results clearly show the importance of this gene. Through our studies on how HLS7 works, we have identified another gene, M44, which may be important in regulation of HLS7 and also plan to investigate is function. Finally, HLS5 has similarities to a group of molecules called transcription factors which are known to be key regulators blood development. Clearly, analysis of this gene will further our knowledge in this field.Read moreRead less
The Developmental Hierarchy Of Haemopoietic Lineage Relationships
Funder
National Health and Medical Research Council
Funding Amount
$192,000.00
Summary
The blood cells are all the progeny of a very rare stem cell, that is thought to reside in the bone marrow. The stem cell maintains itself throughout the life span of the individual as well as generating the billions of more mature cell types required in the blood. However the processes and stages that immature cells pass through from the stem cell to ultimately a mature functional blood cell such as a lymphocyte remain disputed. This study aims to determine to relationship of the various blood ....The blood cells are all the progeny of a very rare stem cell, that is thought to reside in the bone marrow. The stem cell maintains itself throughout the life span of the individual as well as generating the billions of more mature cell types required in the blood. However the processes and stages that immature cells pass through from the stem cell to ultimately a mature functional blood cell such as a lymphocyte remain disputed. This study aims to determine to relationship of the various blood cell progeny with each other and thus to provide a lineage map of the system. To do this we will isolate precursors at various stages along the developmental pathways and determine their capabilities to produce the normal range of progeny. We will then use a number of genetically altered mouse strains to assess the genes involved in this process. These studies will help provide an underlying scientific basis to the attempts to development a number of stem cell therapies that are aimed at boosting or directing stem cell production in procedures such as bone marrow transplantation for leukemia and immune deficiency. In addition a number of characterized human blood malignancies seem to have developed along aberrant pathways indicating that inappropriate lineage specification may be a factor in cancer.Read moreRead less
Mechanisms Underlying Growth, Lineage Commitment And Differentiation Of Liver Progenitor Cells
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Liver disease is a serious health problem. Viral hepatitis, obesity and alcohol can result in end-stage liver disease. Organ transplant is the only treatment available. A widening gap between organ donations and recipients mandates alternative treatments are developed. Cell transplantation and artificial liver devices are alternatives which can use liver progenitor cells. We will investigate how factors grow and convert them into liver cells for treating liver disease patients.
Discovery Of Novel T Cell Oncogenes By Using A Functional Retroviral CDNA Library Screen.
Funder
National Health and Medical Research Council
Funding Amount
$692,470.00
Summary
T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is ....T cells mature in an organ called the thymus which is located on top of the heart. Blood borne T cell precursors enter the thymus after being resident in the bone marrow. T cell leukaemia is a disease where a blood cell that is committed to becoming a T cell is blocked from maturing into a functional cell. Instead, the leukaemic immature T cell uncontrollably divides to make endless non-functional copies of itself. As a result, normal functional T cells are outcompteted and the immune system is crippled. Patients generally die due to opportunistic infection. The molecular causes of T cell leukaemia are slowly being discovered. Up to 50% of all human T cell leukaemias overexpress SCL-TAL-1. Other T cell leukaemia-causing genes (oncogenes) include Ras and Notch. Current leukaemia treatments include chemotherapy and bone marrow transplants but even these fail ~30% of the time. Consequently, all T cell oncogenes need to be discovered so that disease-specific treatments can be generated. This proposal will utlise a functional retroviral cDNA library screen to uncover novel T cell lineage commitment genes and T cell oncogenes. This will be accomplished by constructing a coloured [GFP] cDNA library (a library of genes) that will be transfected (inserted) into immature T cells that cannot develop down the T cell pathway owing to the lack of a crucial gene (Rag-1). The T cell oncogene Ras and the T cell lineage commitment gene Notch can move cells past the Rag-1 block. If there is a gene in the cDNA library that can compensate for the lack of Rag-1 and allow the cells to mature we will detect it using high speed flow cytometryic cell sorting (like sieving weevils from flour very quickly). Once we find this cell we will isolate the gene using the colour tag. The potential oncogenes uncovered will provide the foundation for next generation drug development that targets each leukaemia based on its cause.Read moreRead less
Role Of Common Genetic Variation Driving Single Cell Transcriptional Heterogeneity Across The Cardiomyocyte Lineage
Funder
National Health and Medical Research Council
Funding Amount
$882,698.00
Summary
In human tissues, most mature cells develop by differentiation from pluripotent stem cells. As they undergo differentiation, their transcriptional activity changes dramatically. Many of the genetic causes for these changes are unknown, which limits research in the use of stem cells for treating and modelling disease. This proposal addresses this problem with cardiac muscle cell differentiation by utilising recent developments in biotechnology that enables individual cells to be sequenced.