Local Microvascular Regulatory Mechanisms In Diabetes: Relevance To Neuropathy
Funder
National Health and Medical Research Council
Funding Amount
$212,036.00
Summary
In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore norma ....In diabetes mellitus, the excessive levels of sugar in the blood may cause changes in metabolic processes within cells that lead to disturbances in the function of the circulatory and nervous systems. Such disturbances have been shown to occur in the early stages of diabetes and ultimately lead to longterm consequences including poor wound healing (often culminating in limb amputations), increased risk of blindness, kidney disease and heart failure. At present it is not possible to restore normal metabolism, leaving patients at risk of developing complications involving the circulatory and nervous systems. An understanding of the processes involved in the development of such complications would allow alternate treatment strategies to be devised in order to improve the quality of life and life expectancy of diabetic patients. The events leading to abnormalities in the function of the circulatory and nervous systems are uncertain, however, studies have demonstrated that in diabetes there may be an insufficient blood supply to nerves and this would be expected to cause nerve damage. At present, our understanding of the factors involved in regulating blood flow to nerves is limited. The studies described in this proposal are aimed at testing the hypothesis that nerve blood vessels are themselves involved in the regulation of flow through an intrinsic ability to change their diameter in response to tissue demands and that in diabetes alterations in the capacity of nerve blood vessels to constrict or dilate compromises their role in the control of nerve blood flow . Information obtained from these studies will improve our understanding of the early disturbances in the function of circulatory and nervous systems leading to alterations in blood flow which precede the development of overt changes characteristic of the complications associated with diabetes. This will provide insight into developing new treatment strategies for diabetic patients.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.
The Role Of Connexins In Blood Pressure Regulation: Use Of A Conditional Gene Expression System
Funder
National Health and Medical Research Council
Funding Amount
$583,767.00
Summary
Cell coupling through gap junctions is said to play an important role in regulating blood flow and blood pressure. However data obtained from mice, in which specific gap junctions are deleted, may be compromised by compensatory changes in other junctions. We have validated a new method for rapidly and reversibly altering gap junctions in adult mice with oral sugar. This technique will enable us to directly determine whether interference with cell coupling affects blood flow and blood pressure.
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
Intrauterine Growth Restriction And Development Of The Peripheral And Coronary Vasculature
Funder
National Health and Medical Research Council
Funding Amount
$437,176.00
Summary
There have been no studies which have investigated the extent to which fetal substrate restriction and associated fetal growth restriction alter the expression of nerve growth factors which determine the extent of sympathetic innervation of the peripheral vasculature and the interaction of changes within the peripheral and coronary vasculature which may explain the association between fetal growth restriction and the emergence of cardiovascular disease and high blood pressure in later life. Thes ....There have been no studies which have investigated the extent to which fetal substrate restriction and associated fetal growth restriction alter the expression of nerve growth factors which determine the extent of sympathetic innervation of the peripheral vasculature and the interaction of changes within the peripheral and coronary vasculature which may explain the association between fetal growth restriction and the emergence of cardiovascular disease and high blood pressure in later life. These studies ill provide new insights into the lifelong cardiovascular sequelae of a suboptimal intrauterine environment.Read moreRead less
Characterisation Of PAR2 Knockout And Transgenic Mice: Towards Gene Therapy For Epithelia Based Inflammatory Diseases
Funder
National Health and Medical Research Council
Funding Amount
$486,943.00
Summary
Debilitating and sometimes fatal diseases like asthma and rheumatoid arthritis urgently require new approaches for their effective management and hopefully, cure. We have recently discovered that the airways posses a powerful and naturally-occuring protective mechanism which is regulated by unique molecules in the membranes of the lining cells of the air passages. These molecules are called protease-activated receptors, or PARs, and are also found on cells lining the inner surfaces of blood vess ....Debilitating and sometimes fatal diseases like asthma and rheumatoid arthritis urgently require new approaches for their effective management and hopefully, cure. We have recently discovered that the airways posses a powerful and naturally-occuring protective mechanism which is regulated by unique molecules in the membranes of the lining cells of the air passages. These molecules are called protease-activated receptors, or PARs, and are also found on cells lining the inner surfaces of blood vessels and joints as well as in skin. We are fortunate to have strains of mice - a species in which the PAR-mediated protective mechanism is well developed - in which the gene for the most important of the PARs found in the lung, PAR2, is missing. These animals are called PAR2 'knock-outs'. We also have another strain of mouse in which the human PAR2 gene has been inserted back into PAR2 knock-out mice. These animals will allow us to determine the importance of PAR2 in protection against asthma, arthritis, vascular disease and deficiencies in skin healing, as well as how PAR2 might be a more effective protective agent in mice rather than humans. Thus, modification of the human gene to make the protective system work as effectively as in the mouse might provide an effective therapy or cure for diseases of the lungs, joints and skin as well as in vascular diseases.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.
Renal Medullary Blood Flow: Regulation By Paracrine, Endocrine And Neural Factors
Funder
National Health and Medical Research Council
Funding Amount
$410,616.00
Summary
High blood pressure is a condition afflicting more than 10% of our community, and is the leading risk factor for stroke and heart disease. The kidneys play a critical role in control of blood pressure under normal conditions, and probably also in the initiation and maintenance of high blood pressure. This influence is exerted both through the excretion of salt and water, and by the release of substances into the circulation that affect blood pressure (hormones). Recent experiments performed by u ....High blood pressure is a condition afflicting more than 10% of our community, and is the leading risk factor for stroke and heart disease. The kidneys play a critical role in control of blood pressure under normal conditions, and probably also in the initiation and maintenance of high blood pressure. This influence is exerted both through the excretion of salt and water, and by the release of substances into the circulation that affect blood pressure (hormones). Recent experiments performed by us and others have indicated that the inner part of the kidney (the medulla) is critical in these functions, which appear to be regulated by the level of blood flow in the medulla of the kidney. Our recent experiments also show that hormones and nerves have diverse effects on blood flow in the different regions of the kidney, showing that these factors can differentially affect blood pressure depending on their effects on medullary blood flow. Importantly, these hormones and nerves do not act in isolation, but act in concert, and in association with so called 'second messenger' systems that act locally to directly affect the contraction of muscle in blood vessels, and so blood vessel size. The experiments described in this application are aimed at determining how circulating and locally acting hormones, and the nerves in the kidney, interact together to control blood flow in the different regions of the kidney. This will help us understand how blood flow to the medulla of the kidney is regulated normally, so that we can begin to understand how malfunction of these systems can contribute to the development of high blood pressure.Read moreRead less
Myoendothelial Gap Junctions: Their Composition And Role In Vasodilator Responses Attributed To EDHF
Funder
National Health and Medical Research Council
Funding Amount
$282,750.00
Summary
Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important ....Cardiovascular disease, including coronary heart disease and stroke, continues to be the major cause of death in Australia and hypertension is a significant risk factor. The endothelium, which lines blood vessels of all sizes, is critical to the control of blood flow to the organs of the body. Endothelial cells release factors which can cause blood vessels to constrict or to relax, thus decreasing or increasing blood flow, respectively. Under normal conditions, the endothelium is more important as a source of relaxing factors, while under hypertensive conditions, the balance is shifted in favour of the release of constricting factors. Thus, restoration of the vasodilatory function of the endothelium is seen as an important new therapeutic target in the treatment of vascular disorders. Present data suggests that the action of one of the major endothelial derived vasodilatory factors, the so-called endothelium-derived hyperpolarizing factor, EDHF, requires the presence of particular structures within the vascular wall, but little is known about the molecules of which they are comprised. We have identified two unique situations, during development and during hypertension, when these structures are present in vessels in which they are absent in normal adults. We will use gene microarrays to identify the specific molecules involved in these structures and use physiological studies to test the role of these proteins and structures in vasodilatory responses. The results of these studies may identify new targets for therapeutic intervention to restore the action of EDHF in hypertension.Read moreRead less