MYOCARDIAL NEOVASCULARIZATION FOR ISCHEMIC HEART DISEASE USING BONE MARROW-DERIVED ANGIOBLASTS
Funder
National Health and Medical Research Council
Funding Amount
$577,400.00
Summary
Congestive heart failure remains a major public health problem. In Western societies heart failure is primarily the consequence of a previous myocardial infarction. We have recently identified certain cells in the bone marrow of adult humans that can cause new blood vessel development in the heart after infarction, protecting the heart muscle cells against death and preventing heart failure. Since the cardiovascular diseases that are most likely to benefit from treatments utilizing adult bone ma ....Congestive heart failure remains a major public health problem. In Western societies heart failure is primarily the consequence of a previous myocardial infarction. We have recently identified certain cells in the bone marrow of adult humans that can cause new blood vessel development in the heart after infarction, protecting the heart muscle cells against death and preventing heart failure. Since the cardiovascular diseases that are most likely to benefit from treatments utilizing adult bone marrow-derived endothelial progenitors, or angioblasts, predominantly affect aging individuals, critical questions that must be addressed are whether advanced age and-or progression of cardiovascular disease reduce the total numbers and-or the functional activity of such cells. In the current proposal we will investigate the relationship between increasing age or progression of ischemic heart disease and changes in the number and in vivo biologic properties of human angioblasts. Patients at various ages and stage of cardiovascular disease will be studied. Angioblast numbers will be quantitated in freshly obtained bone marrow cells. The ability of purified angioblasts to be targeted to the ischemic heart will be studied by labeling the angioblasts with a radioactive tracer and measuring tracer uptake in the heart at various time points after intravenous infusion of the cells. Finally, angioblast functional capacity will be evaluated using standard measurements of heart function before and at various time points after reinfusion of cells into the donor. In Aims 2 and 3 of this proposal we will focus our investigations on the potential use of angioblast therapy for reversal of established chronic heart failure in our animal models. Specifically, we will investigate whether induction of neovascularization results in cardiomyocyte regeneration and explore novel strategies to augment heart muscle regeneration by increasing angioblast trafficking to the damaged myocardium .Read moreRead less
Bone Marrow Endothelial Stem Cells Have The Capacity To Form Both The Endothelial And Haemopoietic Hierarchies
Funder
National Health and Medical Research Council
Funding Amount
$1,452,856.00
Summary
Blood cell formation is hierarchically organised; with hemopoietic stem cells (HSC) responsible for producing mature circulating blood cells. HSC reside in marrow near blood vessel cells. Although these play a key role in HSC regulation their origin in adults is poorly understood. We have demonstrated the existence of adult marrow vessel stem cells at the apex of a parallel hierarchy. Our objective is to characterise these in mice and humans and determine their role in blood malignancies.
Role For Sphingosine Kinase-1 In Endothelial Progenitor Cell Survival And Differentiation.
Funder
National Health and Medical Research Council
Funding Amount
$294,205.00
Summary
Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand th ....Lay description: Collectively, diseases of the vascular system contribute immensely to the burden of health care in Australia. Notably, abnormal blood vessel formation and function (angiogenesis) has been identified as a major cause or contributor to the vascular complications associated with inflammation, cancer, rheumatoid arthritis and diabetes. Endothelial cells are one of the principle cells of blood vessels forming a barrier between the blood and tissues. This project aims to understand the process whereby mature endothelial cells are formed and how replacement of damaged endothelial cells is normally achieved. Stem cell therapy is considered the new frontier for the treatment of many diseases. Understanding how endothelial progenitor cells differentiate to mature endothelial cells and the signals which operate inside the cell may allow therapeutic manipulation of key target moecules in order to limit or control inflammation, tumourigenesis, rheumatoid arthritis and diabetic retinopathy. Our results suggest that one target maybe the enzyme sphingosine kinase.Read moreRead less
Contribution Of Bone Marrow-derived Cells To Renal Fibrosis And Elucidation Of Cell Signalling Mechanisms
Funder
National Health and Medical Research Council
Funding Amount
$427,703.00
Summary
This study investigates the contribution of bone marrow-derived adult stem cells to the development of renal scarring, an important process proceeding to end-stage renal disease (ESRD). There is increasing evidence demonstrating that bone marrow (BM)-derived cells can transform into renal cells and participate in the repair of damaged renal blood vessels. Our recent study demonstrated BM-derived stem cells can also transform to renal myofibroblasts, the major cell type that contributes to the de ....This study investigates the contribution of bone marrow-derived adult stem cells to the development of renal scarring, an important process proceeding to end-stage renal disease (ESRD). There is increasing evidence demonstrating that bone marrow (BM)-derived cells can transform into renal cells and participate in the repair of damaged renal blood vessels. Our recent study demonstrated BM-derived stem cells can also transform to renal myofibroblasts, the major cell type that contributes to the development of kidney scarring. This suggests that BM-derived adult stem cells have dual roles: to repair or worsen the development of renal scarring. The present study investigates this adult stem cell's transformation and explores the potential measures to enhance the benefits and to block the harmful roles from these adult stem cells. The importance of BM-derived stem cells in the repair of damaged kidney will be determined and thus will provide preliminary insights into the future utilization of BM-derived stem cells in the treatment of chronic renal disease. Understanding the dual roles of BM-derived stem cells in experimental renal scarring, will lead us to question our current thinking and approaches to the treatment and management of renal fibrosis, and perhaps fibrosis in other organs. Evidence of two opposite roles which BM-derived adult stem cells play in the process of renal scarring may be helpful not only for the design of novel therapies to prevent or retard the progression of renal fibrosis, but also for manipulating adult stem cells for the treatment of renal disease.Read moreRead less
Single-chain Antibodies For Directed Stem Cell Homing And Targeting Of Effector Cells In Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$596,677.00
Summary
Regenerative cellular therapy e.g. with adult stem cells is a promising novel medical therapy. However, until now there is no reliable method to direct cells to areas where they are needed. We aim to develop a biotechnological approach based on genetically tailored antibody molecules that will allow cell targeting. As a pilot project we will test whether this approach improves lipid deposition and hardening of arteries.
Understanding The Role Of Cell Death In Blood Vessel Regression And Regrowth
Funder
National Health and Medical Research Council
Funding Amount
$468,059.00
Summary
Blood vessels are essential to distribute oxygen and nutrients throughout our bodies, and as such, disruptions to normal blood vessel behaviour can have significant impacts on health. This research is aimed at understanding how blood vessel networks can regrow after damage in order to maintain healthy blood supply to a tissue. This work will be particularly relevant to diseases where blood vessel loss or inappropriate blood vessel growth occur.
Haematopoietic Stem Cells From Human Pluripotent Stem Cells: The Future Of Bone Marrow Transplantation
Funder
National Health and Medical Research Council
Funding Amount
$763,845.00
Summary
Blood stem cell transplantation is a vital therapy for patients with leukaemia following chemotherapy or for patients with bone marrow failure. Because many patients lack a donor, there is a need for an alternate source of stem cells. My laboratory will make blood stem cells from human pluripotent stem cells that will treat patients needing a transplant and will be a useful research tool to help us to understand what goes wrong in the blood system in a range of illnesses.
How Is Lipoprotein Disposition Influenced By Fenestrae In The Hepatic Sinusoidal Endothelium?
Funder
National Health and Medical Research Council
Funding Amount
$310,500.00
Summary
Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully d ....Understanding lipoprotein metabolism is critical for the prevention of vascular disease. The liver is the main site for lipoprotein metabolism. The initial step in the metabolism of lipoproteins by the liver is their transfer across the liver sinusoidal endothelial cells from the blood to the liver cells. Sinusoidal endothelial cells contain pores called fenestrae that are thought to allow direct passage of large substances and thus filter lipoproteins on the basis of size. We propose to fully define the role of fenestrae in the ultrafiltration of particles such as lipoproteins and microspheres. This will confirm that ultrafiltration by fenestrae in the liver endothelium is an important biological process akin to filtration by the kidney, and relevant for lipoprotein metabolism. We will determine whether oxidative stress, which generates large gaps in the sinusoidal endothelium, increases the transfer of lipoproteins into the liver. This provides a novel mechanism for fatty liver that follows toxic liver injury, and hence, a therapeutic target for this condition. We will determine whether loss of fenestrae induced by the synthetic non-ionic surfactant, pluronic 407, reduces transfer of lipoproteins. This is an entirely novel mechanism and risk factor for hyperlipidaemia. Finally we will investigate lipoprotein (a) which is a potent risk factor for vascular disease. We will assess with lipoprotein (a), through binding other lipoproteins and increasing their size, impedes their transfer through the fenestrations for subsequent hepatic metabolism. From the basic perspective, these studies will prove that fenestrations in the liver endothelial cell are an ultrafiltration system that is significant for lipoprotein metabolism. From the clinical perspective, the studies will generate novel mechanisms for impaired hepatic metabolism of lipoproteins as well as indicating that fenestrae are a potential target for the development of lipid-lowering pharmacotherapies.Read moreRead less