The Role Of Ap2a2 In Self-renewal Of Haematopoietic And Leukemic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$579,171.00
Summary
The daily replenishment of the blood system is dependent on the blood stem cell. A unique property of these stem cells is self-renewal where the stem cell function is preserved, whilst other daughter cells continue to divide. Our research investigates the molecular mechanisms that regulate stem cell self-renewal. This work has potential clinical application on at least two levels: expansion of stem cells for transplantation, and for attacking abnormal cancer cell self-renewal pathways.
Transcriptional Regulation Of Haematopoietic Stem Cell Development
Funder
National Health and Medical Research Council
Funding Amount
$566,470.00
Summary
Cancer initiating cells acquire stem cell characteristics and self renew within a supportive environment that helps maintain and propagate malignant tumours. Identifying the normal hierarchy of gene regulation within blood stem cells and designing therapies that target key transcription factors (proteins that control other genes) that are over expressed in cancer stem cells is the ultimate goal.
The overall incidence of primary brain tumours in the Western world is 10 per 100,000 people. Unlike many other tumours, these occur in patients of all ages and comprise the second most common tumour type among children and young adults. Most brain tumours remain incurable. We are using our expertise in the field of neural stem cell research to characterise tumour cells responsible for resistance to treatment, with the final goal of identifying new targets for therapeutic intervention.
Using Drosophila To Define An Epithelial Cancer Stem Cell
Funder
National Health and Medical Research Council
Funding Amount
$552,988.00
Summary
Cancer is a complex disease that involves the mis-regulation of genes and aberrant cell-cell communication . To help gain a better understanding of these processes it is possible to examine simpler systems. This proposal uses a unique cancer model in flies to understand how a change in cell fate can endow cells with the ability to continue dividing and invading surrounding tissues, thus driving cancer development.
Hematopoietic Transplants From Autologous Pluripotent Cell Sources
Funder
National Health and Medical Research Council
Summary
This proposal investigates the utility of two types of patient-derived stem cells for transplantation into blood. These are induced pluripotent stem cells that are reprogrammed from specialized tissues such as skin cells, and stem cells derived using the genetic material of oocytes or sperm only ( one-parent embryos). Using the mouse, we are looking at the ability of these cells to form normal blood lineages after transplantation, and to repair blood in a mouse model for beta-thalassemia.
C-myb Regulates Stem-progenitor Cell Cycle Entry In Colonic Crypts Providing Insights Into Colo-rectal Carcinogenesis
Funder
National Health and Medical Research Council
Funding Amount
$386,020.00
Summary
During a human's life time the colon or large bowel produced an extraordinary volume of cells. This requires almost unimaginable numbers of cell divisions. We are investigating the role of a gene (c-myb) that we propose is one of the key regulators of normal colon growth and function. It is expressed in the base of the functional unit of the colon called the colonic crypt. The base contains the stem cell population which give rise to all the crypt cells. We have generated and gathered a unique a ....During a human's life time the colon or large bowel produced an extraordinary volume of cells. This requires almost unimaginable numbers of cell divisions. We are investigating the role of a gene (c-myb) that we propose is one of the key regulators of normal colon growth and function. It is expressed in the base of the functional unit of the colon called the colonic crypt. The base contains the stem cell population which give rise to all the crypt cells. We have generated and gathered a unique and comprehensive set of mutant mice that have various degrees of dysfunction of the c-myb gene. We will study the colons of these mice to determine how c-myb regulates cell growth. We will also investigate these mice under stress conditions like that associated with cancer therapies like radiation treatment. Understanding such genes will improve the management of cancer patient how suffer gastro-intestinal side effects such as diarrhoea, perhaps hyper-proliferative disorders like inflammatory bowel disease and finally colon cancer where complete loss of cell growth is a feature.Read moreRead less
Functional Studies On The Role Of DNp73 In Stem Cells And Cancer
Funder
National Health and Medical Research Council
Funding Amount
$428,838.00
Summary
This project investigates the role of the p73 gene in regulating stem cells and facilitating intestinal cancer formation. We hypothesize that when a particular form of this gene (DNp73) is upregulated it prevents differentiation of stem cells and promotes tumour formation. We combine novel approaches in mice and fruit flies to examine the function of DNp73 in stem cells with analysis of human tumour samples. These studies may identify a new target for tumour therapy.
The Role Of The Transcriptional Regulator, Taube Nuss, In Stem Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$267,200.00
Summary
Cells are born, mature, age, are eliminated and replaced by new cells in many organ systems throughout life. Stem cells constitute the reserve of cells set aside for this regeneration process and also for the repair of damaged tissue. During embryonic development transient stem cell populations exist for the generation of tissues. Stem cells are capable of self-renewing proliferation and are able to give rise to mature cell types (differentiation). The regenerative capacity of stem cells could p ....Cells are born, mature, age, are eliminated and replaced by new cells in many organ systems throughout life. Stem cells constitute the reserve of cells set aside for this regeneration process and also for the repair of damaged tissue. During embryonic development transient stem cell populations exist for the generation of tissues. Stem cells are capable of self-renewing proliferation and are able to give rise to mature cell types (differentiation). The regenerative capacity of stem cells could potentially be used in the treatment of degenerative diseases like Parkinson s disease and muscular dystrophy, if we knew enough about their function. If stem cell proliferation and differentiation into mature cell types could be influenced in a clinical setting, stem cells could be encouraged to replace diseased or dead cells more efficiently than they do normally. In sharp contrast to the potential medical benefits that could be derived from stem cells, our understanding of the molecular mechanisms controlling self-renewal and maintenance of a wide differentiation potential are very limited. We have isolated a new gene, Taube nuss (- empty nut), which is essential for the survival of the first transient stem cell population in the early embryo. In mice, lack of Taube nuss protein results in the death of these stem cells, whereas the differentiated cells of the same embryos survive. Taube nuss is a member of a protein complex called transcription initiation complex. We plan to investigate if Taube nuss plays a role in other stem cell populations. If this is the case, we will not only be able to identify Taube nuss as a new regulator of stem cell function. We would also be able to demonstrate a new regulatory mechanism, namely the involvement of specific transcription initiation complexes in the control of stem cell function.Read moreRead less
Regulation Of The Drosophila C-Myc Homologue In Stem Cell Growth And Division.
Funder
National Health and Medical Research Council
Funding Amount
$613,397.00
Summary
The mechanisms controlling stem cell growth and division require elucidation if we are to use stem cells in regenerative medicine and find cancer treatments. Due to experimental limitations such mechanisms are largely unknown in humans. We aim to use the vinegar fly as a model system to understand the importance of microenvironment to cancer gene control in stem cells. We will identify the secreted signals, from the neighbouring cells, required to control cancer initiation in stem cells.
The Role Of Hyaluronic Acid, CD44 And Osteopontin In Haemopoietic Stem Cell Biology
Funder
National Health and Medical Research Council
Funding Amount
$472,062.00
Summary
Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid (HA), CD44 and osteopontin play key roles in the localisation of HSC with ....Marrow and microenvironmental cell (MC) interactions play a central role in bone marrow (BM) cell localisation and regulation. Specifically, the regulation of primitive blood cells (HSC) is affected by their locality and their expression of a wide repertoire of cell adhesion molecules. This project is based upon the unique observations made in the applicants laboratory demonstrating that the three molecules hyaluronic acid (HA), CD44 and osteopontin play key roles in the localisation of HSC within the BM following transplantation and in regulating their development into mature blood cells. Encapsulating the concept of highly specific, local interactions regulating blood cells is the 'niche' hypothesis in which MC form a specific 'niche'. The current inability to identify HSC in situ makes it impossible to analyse either their distribution or molecules that regulate this process. Circumstantial evidence suggests the presence of HSC 'niches' in close association with the bone. Using a novel approach based on BM transplantation to track cells lodging in the BM, we were the first to report that the lodgement of a transplanted HSC is not a random process, but results in cells of donor origin migrating to the bone-marrow interface. The presence of HA and CD44 on the HSC and CD44 and ostepontin in the marrow microenvironment are critical for this pattern of lodgement. In addition, we now have evidence that HA and osteopontin are important in the maintenance of HSC in their primitive state. This proposal aims to confirm the critical roles and interactions of these three molecules in HSC biology.Read moreRead less