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.
Cellular And Molecular Mechanisms Of Human Choroidal And Retinal Vascularisation
Funder
National Health and Medical Research Council
Funding Amount
$288,210.00
Summary
The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness h ....The abnormal growth of new blood vessels is a major cause of blindness in people of all ages. In premature infants, changes in retinal blood vessels results in Retinopathy of Prematurity (ROP) the leading cause of infant blindness in the world. In older adults with age-related macular degeneration (ARMD), vessels in the choroid can grow into and under the retina where they can cause catastrophic loss of vision. This association of abnormal vessel growth with the most common causes of blindness has motivated the search for a better understanding of how blood vessel growth in the eye is controlled in healthy tissues and how these controls fail in disease. Our proposal addresses this issue directly. Recent work shows that this neovascularization is not only a response to a rise in the local concentration of molecules that induce such angiogenesis, but also requires a fall in the levels of endogenous molecules that inhibit angiogenesis. Our study will investigate the expression of newly identified angiogenic growth factors (VEGFs) and their receptors as well as angiogenic inhibitors (VEGI and PEDF) in the developing and adult human retina and choroid. We will examine the mechanisms by which the human choroid is formed. Our preliminary results suggests the novel insight that vasculogenesis (the formation of blood vessels via transformation of vascular precursor cells) plays a major role the formation of both the human retina and choroid. Further, these exciting results suggest involvement of novel growth stimulators and inhibitors previously not known to play a role in these processes. Our studies will lead to new insights regarding the vascular growth factors and inhibitors that drive this process, thus leading to a rational basis for new therapeutic targets for the treatment of ARMD. The rapid aging of the Australian population and the consequent predicted doubling of ARMD incidence in the next 20 years demonstrates the urgency of our studies.Read moreRead less
Rationale For Non-invasive Treatment Of Retinopathy Of Prematurity: Dark Rearing As A Means Of Mimicking Physiological Vascularisation
Funder
National Health and Medical Research Council
Funding Amount
$413,900.00
Summary
We aim to develop a new, non-invasive and cost-effective treatment for the disease Retinopathy of Prematurity, the leading cause of childhood blindness across the globe. We intend to test our hypothesis that raising neonates in conditions of total darkness and high oxygen will closely mimic conditions for inducing normal retinal vascular development, and thus prevent the initiating event of the disease. Ultimately, the project intends to lay the groundwork for a translation to the human conditio ....We aim to develop a new, non-invasive and cost-effective treatment for the disease Retinopathy of Prematurity, the leading cause of childhood blindness across the globe. We intend to test our hypothesis that raising neonates in conditions of total darkness and high oxygen will closely mimic conditions for inducing normal retinal vascular development, and thus prevent the initiating event of the disease. Ultimately, the project intends to lay the groundwork for a translation to the human condition.Read moreRead less
The Identification Of A Novel NIDDM Susceptibility Gene Localised To Human Chromosome 12q
Funder
National Health and Medical Research Council
Funding Amount
$438,055.00
Summary
Non-insulin dependent diabetes mellitus (adult-onset diabetes) is very common in Australia and is a major public health problem. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 3% of the Australian population have adult-onset diabetes, and very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that an inherited tende ....Non-insulin dependent diabetes mellitus (adult-onset diabetes) is very common in Australia and is a major public health problem. It is a leading cause of kidney failure, blindness, heart attacks, strokes and amputations. Over 3% of the Australian population have adult-onset diabetes, and very few Australians have not been touched in some way by the shadow of diabetes. The precise cause of diabetes is unknown, however we do know that it tends to run in families, indicating that an inherited tendency is important. By finding genes which cause diabetes we have the opportunity to unravel much of the mystery of this condition. This research program will find genes which cause diabetes by searching for them in large pedigrees in which many family members are affected by diabetes. Finding the genes which cause diabetes will have a significant impact in at least three major ways. Firstly, it will increase our understanding of the disease process. Secondly, it will be possible to develop tests to identify people at risk of diabetes at a very early stage so that therapy can be introduced and complications averted. Thirdly, it will be possible to develop new and more effective approaches for the prevention and treatment of diabetes.Read moreRead less
Regulation Of Vascular Tone By Indoleamine 2,3-dioxygenase
Funder
National Health and Medical Research Council
Funding Amount
$457,267.00
Summary
As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other condit ....As part of their normal function, blood vessels dilate and contract, for example in response to the pulsative force with which our heart pumps the blood around the circulation. Blood vessels produce several different chemicals that cause vessel relaxation, and these vary depending on several factors, such as the blood vessel involved, its diameter and precise location within our body. In addition to responding to the pulsative nature of blood flow, blood vessels also respond to many other conditions, including certain diseases, so that it is not surprising that many of the commonly used cardiovascular drugs target to change blood vessel tone, either increasing or decreasing blood pressure, depending on the circumstances involved. The present application is based on the discovery, in the mouse, that during a systemic infection a specific protein is induced in the cells that line blood vessels. This protein degrades a certain amino acid into a novel chemical, called kynurenine. We observed that kynurenine has previously unrecognised vessel-relaxing properties. The present project will investigate the importance of kynurenine formation as a novel pathway in the regulation of vascular tone. Mice, in which the activity of the kynurenine-producing protein will be modulated (both up and down) will be used in conjunction with blood pressure and other relevant measurements. In addition, the role of a unique molecule, called superoxide anion radical, in the production of kynurenine by the protein will also be tested. If our results confirm that the protein and kynurenine are indeed involved in regulating vascular tone, our research could have tremendous impact on many aspects of normal physiology as well as cardiovascular diseases that remain the major single cause of death in Australia.Read moreRead less
Epithelial - Stromal Interactions In Pancreatic Cancer: Role Of Pancreatic Stellate Cells
Funder
National Health and Medical Research Council
Funding Amount
$425,750.00
Summary
The pancreas is the major digestive organ in the body. It is located in the abdomen, draped across the spine behind the stomach. Pancreatic cancer is a leading cause of death in this country and in Western Society in general. Most patients with this disease survive only a few months after diagnosis. Even for those in whom a curative operation is undertaken, survival is poor. Chemotherapy and radiotherapy (alone and in combination) result in, at best, limited benefit. Clearly, there is a need for ....The pancreas is the major digestive organ in the body. It is located in the abdomen, draped across the spine behind the stomach. Pancreatic cancer is a leading cause of death in this country and in Western Society in general. Most patients with this disease survive only a few months after diagnosis. Even for those in whom a curative operation is undertaken, survival is poor. Chemotherapy and radiotherapy (alone and in combination) result in, at best, limited benefit. Clearly, there is a need for novel approaches to this lethal disease. The proposed project involves an examination of the local tissue reaction around pancreatic cancer. This tissue reaction is usually prominent and the cells involved may determine the extent of local and distant spread of the cancer. Modulation of this tissue reaction may limit pancreatic cancer growth and thus improve outcome.Read moreRead less
We have found that during infection a protein (called IDO) is made in cells lining arteries. IDO degrades tryptophan into kynurenine, which can open arteries, while blocking IDO increases blood pressure. We will now study the importance of this metabolic pathway in various diseases using mice with either absent or high levels of IDO, and also perform the first such studies in human blood vessels. We predict the research to have a tremendous impact on our understanding of cardiovascular diseases.
NADPH Oxidase In Pathological Angiogenesis In Solid Tumours And Retina
Funder
National Health and Medical Research Council
Funding Amount
$581,989.00
Summary
Understanding blood vessel growth has profound clinical implications for many diseases. Blocking vessel growth is a promising strategy for treatment of cancer and eye complications accompanying diabetes, whereas treatments to stimulate new vessel growth will treat ischemic disorders ie. heart attack and stroke. Here we investigate whether targeting an enzyme that grows blood vessels has potential for making drugs to stop tumor growth or eye damage that occurs with diabetes and premature births.