Lung Epithelial Stem Cells In Chronic Respiratory Disease
Funder
National Health and Medical Research Council
Funding Amount
$586,965.00
Summary
The World Health Organisation estimates that by 2020, 12 of 68 million deaths worldwide will be attributed to lung disease with Chronic Obstructive Pulmonary Disease ranked the 3rd leading cause of death. Current therapies are palliative, providing symptomatic relief but no prospect of cure. In this project, we aim to determine how the ability of lung stem cells to repair the lung is compromised in disease in order to develop innovative therapies to arrest or reverse the disease process.
Prediction Of Clinical Radiosensitivity Caused By Ionising Radiation During Radiotherapy.
Funder
National Health and Medical Research Council
Funding Amount
$447,750.00
Summary
Around one to five percent of cancer patients suffer from significant side effects in normal tissue exposed to ionizing radiation during radiotherapy. Although radiotherapy is an effective therapy for cancer treatment, the amount of radiation is generally restricted to minimize the incidence of these severe side effects (radiosensitivity). This means that individuals who don't have radiosensitivity are not getting the dose of radiation that would be most beneficial. A major goal of radiation bio ....Around one to five percent of cancer patients suffer from significant side effects in normal tissue exposed to ionizing radiation during radiotherapy. Although radiotherapy is an effective therapy for cancer treatment, the amount of radiation is generally restricted to minimize the incidence of these severe side effects (radiosensitivity). This means that individuals who don't have radiosensitivity are not getting the dose of radiation that would be most beneficial. A major goal of radiation biology research is to develop efficient predictive measures that could identify radiosensitive individuals prior to treatment. This predictive ability would enable the individualisation of radiotherapy radiation doses, which should result in improvement of tumour control rates and a reduction in the incidence of side effects associated with radiotherapy. We aim to understand radiosensitivity at the molecular level using the powerful technology of microarrays. Using microarray technology, thousands of genes can be tested for expression activity simultaneously. We have a unique tissue bank established from many radiosensitive and non-sensitive control radiotherapy patients. The use of microarray technology on samples from this unique tissue bank may enable the gene expression pattern of individuals that display radiosensitivity to be distinguished from the rest of the population. In conjunction, two additional tests will be used to determine who is susceptible to radiosensitive reactions which include assessment of a DNA repair pathway and assessment of the length of the telomeres (Caps on the ends of the chromosomes), both of which have been shown to be involved with radiosensitivy. This experimentation will hopefully lead to the development of a predictive assay for use in the clinic for cancer patients prior to receiving radiotherapy.Read moreRead less
Growth Factors And Regulatory Genes Controlling Male Spermatogonial Proliferation And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$354,536.00
Summary
In newborn and prepubertal boys the testis contains germ cells which are at a premature stage of development and very suseptible to degeneration especially if the testes fail to descend to the scrotum. The molecules which are responsible for the health of these germ cells have been unknown and only recently the way has been opened for direct study of these factors. This has been made possible by a new assay, developed in our labarotory, in which we can grow these germ cells under defined conditi ....In newborn and prepubertal boys the testis contains germ cells which are at a premature stage of development and very suseptible to degeneration especially if the testes fail to descend to the scrotum. The molecules which are responsible for the health of these germ cells have been unknown and only recently the way has been opened for direct study of these factors. This has been made possible by a new assay, developed in our labarotory, in which we can grow these germ cells under defined conditions. This step forward has highlighted some areas of knowledge which need further research such as identification of the processes which stimulate gonocytes to grow and divide. We need to test growth factors, somatic cell factors and also isolate new genes which are associated with germ cells and their growth. This knowledge will have outcomes in two major areas. First, the new findings could be applied to treatment of infertility resulting from undescended testes in which a stimulus could be given to make the germ cells grow again. Second, work in developing longer term culture of germ cells coupled with introduction of mutations will enable us to make mutant mice with a specific gene abnormality, similar to transgenic or gene knockout mice. This technological development would prove less expensive and time consuming with more reproducible and direct outcomes. Mutant mouse technology is a powerful tool to determine the effects of individual genes in the whole animal (mouse).Read moreRead less
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.
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.
Role Of The Hypoxia-inducible Transcription Factor HIF-1a In Controlling Haematopoietic Stem Cell Fate
Funder
National Health and Medical Research Council
Funding Amount
$586,428.00
Summary
Haematopoietic stem cells (HSCs) reside in the bone marrow (BM) and make all immune and blood cells. We have found that, in the areas of the BM where HSC normally live, the level of oxygen is very low (hypoxia) and decreases even further when HSC are forced to move into the blood in order to be collected for transplantation. This project is to better understand how oxygenation of the BM controls HSC behaviour and properties, and to evaluate its impact on HSC transplantation.
Kidney Mesenchymal Stem Cells In Tubular Development, Repair And Turnover.
Funder
National Health and Medical Research Council
Summary
In Australia, 11.3% of deaths are associated with chronic kidney disease with >$1 billion per annum spent on treating this condition. At present, only dialysis and transplantation are available to treat end stage kidney disease. We have found a kidney stem cell population in both human and mouse that can form new epithelial structures. In this project, we will investigate the normal role played by these kidney stem cells and examine whether they can contribute to kidney regeneration.
Role Of Selectins And Their Receptors In The Regulation Of The Haemopoietic System
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
The production of blood cells occurs in the bone marrow. This process depends on the controlled proliferation and development of rare and multipotent precursors called haemopoietic stem cells, and involves a subtle balance between the positive regulation of proliferation and growth inhibition necessary to prevent blood cell overproduction and leukaemia. We have recently shown that two related proteins expressed at the surface of cells of the bone marrow vasculature negatively regulate blood cell ....The production of blood cells occurs in the bone marrow. This process depends on the controlled proliferation and development of rare and multipotent precursors called haemopoietic stem cells, and involves a subtle balance between the positive regulation of proliferation and growth inhibition necessary to prevent blood cell overproduction and leukaemia. We have recently shown that two related proteins expressed at the surface of cells of the bone marrow vasculature negatively regulate blood cell formation. These proteins, called P-selectin and E-selectin, are essential to regulate the migration of immune cells into lymphoid organs and inflamed tissues. We have found that these selectins also mediate the adhesion of haemopoietic stem cells in the bone marrow vasculature, inhibit their proliferation and kill some of their progeny. This project includes three specific aims to: 1) characterise the role of P-selectin and E-selectin in vivo in the regulation of blood cell formation, 2) understand the molecular mechanisms inside haemopoietic stem cells which are responsible for the growth inhibition and cell death in response to selectins, and 3) identify the receptors which are responsible for these effects of selectins on haematopoietic stem cells. These findings will give us a better understanding of how blood formation is regulated in vivo and how these interactions are perturbed during the emergence of leukaemia.Read moreRead less
The Role Of Hyaluronic Acid In The Biology Of Haemopoietic Stem Cells
Funder
National Health and Medical Research Council
Funding Amount
$392,090.00
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 (CAM). This project is based upon the unique observation made in the applicants laboratory demonstrating that both murine HSC and candidate human HSC synthesize the carbohydrate CAM hyaluronic acid (HA). Moreover w ....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 (CAM). This project is based upon the unique observation made in the applicants laboratory demonstrating that both murine HSC and candidate human HSC synthesize the carbohydrate CAM hyaluronic acid (HA). Moreover we have now accumulated data suggesting a key role for HA in determining the spatial distribution 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 HSCs 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 lodgment of a transplant of HSC is not a random process, but results in cells of donor origin being located at the bone-marrow interface. The presence of HA on HSC was critical for this pattern of lodgment. In addition, we have also accumulated evidence suggesting that HA is important in the maintenance of HSC in their primitive state. This proposal aims to confirm the critical role of HA in HSC biology.Read moreRead less
Role Of Beta-catenin And Its Regulator FAM In Haemopoietic Stem Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$506,500.00
Summary
Haemopoietic stem cells (HSC) are currently the best characterised adult stem cell (SC) population and currently the only SC population used in cellular therapy. Adult HSC reside in the bone marrow and it is generally accepted that these rare cells cycle slowly and maintain themselves by a process involving self renewal. The cellular physiology that underlies HSC self renewal is still to be defined and no single factor has been described which is able to induce substantial proliferation and expa ....Haemopoietic stem cells (HSC) are currently the best characterised adult stem cell (SC) population and currently the only SC population used in cellular therapy. Adult HSC reside in the bone marrow and it is generally accepted that these rare cells cycle slowly and maintain themselves by a process involving self renewal. The cellular physiology that underlies HSC self renewal is still to be defined and no single factor has been described which is able to induce substantial proliferation and expansion of HSC in a defined system while maintaining critical stem cell properties. Like other SC, a critical characteristic of the rare HSC population of cells is their ability to maintain their unique stem cell properties in vivo (the process of self-renewal) while generating more committed cells which will form large numbers of differentiated and specialized mature blood cells. Recent evidence that HSC can repair other organs under some circumstances raises the possibility that this adult SC population could provide an alternative to embryonic stem cells for many stem cell therapies. If this is the case the therapeutic application of HSC becomes significantly broader. Critical to development of such applications will be an understanding of HSC self renewal and development and new approaches to expand this limited cell population. Major progress in this area will require the definition of both the intrinsic and extrinsic mechanisms that control HSC maintenance and self-renewal. Any findings in this area will have major clinical significance and be of enormous benefit to the community. Here we focus on the role of a known intrinsic regulator of SC behaviour (beta-catenin) with the aim of establishing its role in the maintenance of HSC and its regulation by a novel cofactor (FAM). We will determine if the level of beta-catenin is critical in the maintenance and-or differentiation of haemopoietic stem cells and what role FAM plays in this regulation.Read moreRead less