The lining of the uterus is unusual compared to other parts of the adult body in that new blood vessels grow and then breakdown during menstruation every month. The aim of this project is to understand what controls the growth and regression of these uterine blood vessels. This information is of immediate relevance to a number of clinical problems where an ability to either promote or prevent blood vessel growth would be of major advantage. For example, increased blood vessel growth would accele ....The lining of the uterus is unusual compared to other parts of the adult body in that new blood vessels grow and then breakdown during menstruation every month. The aim of this project is to understand what controls the growth and regression of these uterine blood vessels. This information is of immediate relevance to a number of clinical problems where an ability to either promote or prevent blood vessel growth would be of major advantage. For example, increased blood vessel growth would accelerate wound healing, while blocking blood vessel growth would prevent the growth and spread of cancers. Another disorder that could be controlled through preventing blood vessel growth is endometriosis, a disease where cells from the lining of the uterus grow inside the abdomen causing pain and infertility. Endometriosis affects upto 10% of women.Read moreRead less
The Role Of Dysregulated VEGFs In Lymphatic And Non-lymphatic Vascular Malformations
Funder
National Health and Medical Research Council
Funding Amount
$389,486.00
Summary
Vascular malformations are abnormal growths of blood vessels that affect hundreds of children born in Australia every year. They range from small birthmarks to large destructive growths that cause chronic pain, bleeding and major deformity. This is the largest ever study to systematically look for the biological drivers that cause these growths so that drug treatments will ultimately be able to replace surgery as the first line treatment.
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
Beta-Adrenergic Activation: A Double-edged Sword On Cardiac Angiogenesis
Funder
National Health and Medical Research Council
Funding Amount
$365,126.00
Summary
We will test our hypothesis that activation of beta-adrenergic receptors (b-AR) regulates significantly on growth of blood vessels in the heart. While initialy promoting vessel growth, prolonged stimulation of b-AR, a situation seen with diseased hearts, suppresses vessel growth thereby promoting disease progression. This hypothesis is strongly supported by our recent experimental findings and would have important clinical implication on the treatment of patients with heart disease.
The properties of Vegf-B suggest that it may play a role in new blood vessel formation (angiogenesis) especially during the development of the heart. Mice with the Vegf-b gene deleted are viable and fertile but display cardiac dysfunction as the animals age and in experimental conditions of ischemia. Comparison of total gene expression in the hearts of mice lacking Vegf-B with those of normal mice will identify genes involved in blood vessel formation during cardiac development and maintenance. ....The properties of Vegf-B suggest that it may play a role in new blood vessel formation (angiogenesis) especially during the development of the heart. Mice with the Vegf-b gene deleted are viable and fertile but display cardiac dysfunction as the animals age and in experimental conditions of ischemia. Comparison of total gene expression in the hearts of mice lacking Vegf-B with those of normal mice will identify genes involved in blood vessel formation during cardiac development and maintenance. The genes identified will be targets for designing potential new drugs and therapies for cardiovascular disease.Read moreRead less
Effect Of Pregnancy And Pre-eclampsia On Smooth Muscle And Endothelial Cell Function In Arteries Isolated From Women
Funder
National Health and Medical Research Council
Funding Amount
$194,537.00
Summary
During normal pregnancy the blood vessels of the mother become relaxed. This helps to meet the growing demands of the mother at this time and also ensures sufficient blood supply to the developing fetus. Blood vessels are lined by a single cell layer called the endothelium. The endothelium inactivates a variety of circulating agents which cause arteries to contract, and it also produces potent substances that directly relax the muscle cells in the blood vessel wall. Thus the endothelium plays an ....During normal pregnancy the blood vessels of the mother become relaxed. This helps to meet the growing demands of the mother at this time and also ensures sufficient blood supply to the developing fetus. Blood vessels are lined by a single cell layer called the endothelium. The endothelium inactivates a variety of circulating agents which cause arteries to contract, and it also produces potent substances that directly relax the muscle cells in the blood vessel wall. Thus the endothelium plays an important role in the adaptation of the maternal blood vessels to pregnancy. Insufficient blood supply to the placenta somehow triggers myriad processes including endothelial dysfunction, enhanced clotting of the blood and contraction of the maternal blood vessels, which culminates in the serious disorder of pregnancy known as pre-eclampsia. This condition threatens the health of both mother and fetus, and in Australia, is responsible for 15% of direct maternal deaths and 10% of perinatal mortality. The focus of this project is to study the function of the endothelium and the muscle in the artery wall, and how the function of these entities is altered in the natural adaptation to pregnancy and in pre-eclampsia. The general aim of this study is two fold: (1) to determine how endothelial function adapts to pregnancy and how this is compromised in pre-eclampsia (2) to determine how factors released from the endothelium alone, or in combination with changes in inherent muscle function, alter the state of relaxation and contraction of muscle in the blood vessel wall, and the influence of pregnancy and of pre-eclampsia on these. This project will contribute to a greater understanding of the mechanisms that control the relaxation and contraction of blood vessels in normal pregnancy and those mechanisms that are impaired during pre-eclampsia and thus, may facilitate the development of treatments for this serious disorder.Read moreRead less
Optimising Islet Transplantation With Vascularized Tissue Engineering Chambers
Funder
National Health and Medical Research Council
Funding Amount
$451,651.00
Summary
Diabetics have high blood sugar levels because cells in the pancreas known as islets produce too little of the hormone insulin. Most diabetics need daily insulin injections to maintain normal blood sugar levels. Transplanting islets is the most promising way to treat type 1 diabetes, but, apart from the obvious difficulty of rejection of foreign islets, several major problems remain: (1) there are insufficient pancreata (and therefore islets) for transplantation; and (2) the efficiency of delive ....Diabetics have high blood sugar levels because cells in the pancreas known as islets produce too little of the hormone insulin. Most diabetics need daily insulin injections to maintain normal blood sugar levels. Transplanting islets is the most promising way to treat type 1 diabetes, but, apart from the obvious difficulty of rejection of foreign islets, several major problems remain: (1) there are insufficient pancreata (and therefore islets) for transplantation; and (2) the efficiency of delivery of surviving islet transplants is too low. In pilot studies we have grown a new living pancreatic organ in mice by inserting islets from genetically-related mice together with a structural protein matrix, growth factors and blood vessels inside a plastic chamber. The blood vessels maintain nutrition to the islet cells and simultaneously allow insulin to be released into the bloodstream, thus normalising the high blood sugar in diabetics. In Aim 1 of these experiments we will find the optimal way to grow mature islets in blood vessel-containing chambers in diabetic mice, focusing on (a) the best time to add islets to the chamber - 0, 1 or 2 weeks after establishment, (b) the minimum number of islets to effectively normalise blood sugar and (c) how long we can keep islets alive and functional in chambers, examining periods up to 12 months. In Aim 2 we will test the ability of islet stem cells (provided by our co-investigators at Walter and Eliza Hall Institute, Melbourne) to survive in the chambers and to produce sufficient insulin to effectively lower blood sugar levels to normal in diabetic mice. In Aim 3 we will grow human islets in chambers in special diabetic mice that do not reject foreign tissue, in order to confirm similar behaviour of human islets in this controlled environment. Using this data, we hope to create a research model of functioning islets, that is accessible, retrievable and manipulable, for the further study of diabetes and transplantation.Read moreRead less
Understanding Local And Regional Determinants Of EDHF And NO Dysfunction In Resistance Arteries In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$771,295.00
Summary
Diabetes is a serious and increasing health burden worldwide. Most of the sickness and death associated is due to complications arising in the blood vessels. The inner lining of blood vessels in small arteries uses several different mechanisms to ensure proper blood flow, and in diabetes these are impaired. This study will reveal the cellular mechanisms involved and identify pathways for therapeutic intervention to alleviate the debilitating effects of small artery disease.