The Role Of Crim1, A Novel TGFb Superfamily Modulator, In Early Vertebrate Patterning, Vascular And Renal Development.
Funder
National Health and Medical Research Council
Funding Amount
$501,300.00
Summary
The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be dele ....The transforming growth factor (TGF) beta superfamily is a large group of secreted growth factors who play many different roles in normal development of tissues such as the brain, skeleton, heart, kidney, eyes, teeth and limbs. One of the groups within the superfamily, the bone morphogenetic proteins (BMPs), are being used in clinical trials to assist in regrowing bones after fracture. These molecules are also of interest for clinical reasons as growth factors within this family can also be deleterious, with their overexpression leading to conditions such as renal fibrosis and cataract. The activity of these growth factors is regulated by many other proteins, including protein antagonists which bind and inactivate them. It is therefore possible that by understanding these antagonists, we can find new ways of altering TGF beta superfamily activity. We have previously identified a novel protein, Crim1, which we have now shown can bind to TGF superfamily members and can reduce their secretion. We believe that Crim1 plays a role in the patterning of the central nervous system, the development of the blood vessels and the kidneys by regulating the TGFbeta superfamily. In this grant we will be investigating what the effect of disruption to Crim1 is on these organ systems and working out which members of the TGFbeta superfamily it is affecting to cause these effects. To do this, we will knock out the gene in zebrafish and characterise the defects found in a mouse line in which the gene has been disrupted. This may be important in developing new ways of activating or inactiviating these growth factors in a number of clinical conditions.Read moreRead less
Role Of Indoleamine 2,3-dioxygenase In Vascular Disease
Funder
National Health and Medical Research Council
Funding Amount
$271,500.00
Summary
Atherosclerosis and its clinical presentation including heart attack and stroke represent a major source of morbidity and mortality in the developed world, including Australia. Atherosclerosis involves the accumulation of lipid-laden cells in the wall of arteries that generates plaques resulting in a decrease in the lumen of the affected vessel that can impede or block blood flow resulting in clinical complications. The cellular events involved in atherosclerosis are complex. However, increasing ....Atherosclerosis and its clinical presentation including heart attack and stroke represent a major source of morbidity and mortality in the developed world, including Australia. Atherosclerosis involves the accumulation of lipid-laden cells in the wall of arteries that generates plaques resulting in a decrease in the lumen of the affected vessel that can impede or block blood flow resulting in clinical complications. The cellular events involved in atherosclerosis are complex. However, increasing information indicates that atherosclerosis involves an inappropriate response of the immune and inflammatory systems. This proposal plans to investigate the role of a protein, indoleamine 2,3-dioxygenase (IDO) that is increased during inflammation and is important for the regulation of the host's immune system. We propose that increasing IDO activity in inflammatory cells will attenuate the degree of vascular disease by decreasing the overall level of immune activation and inflammation in the blood vessels. We will test this by modulating the expression and activity of this protein in animal models of vascular disease, measure the extent of disease and then elucidate the mechanisms by which the protein acts. The significance of these studies is that they will provide useful information on the inflammatory and immune processes involved in the progression of atherosclerosis and may identify a potential novel target for therapeutic intervention.Read moreRead less
RCT Of Aspirin And Fish Oil For The Prevention Of Thrombosis In Arterio-venous Fistulae For Dialysis Access
Funder
National Health and Medical Research Council
Funding Amount
$1,869,190.00
Summary
This randomised, placebo-controlled clinical trial aims to determine whether the anti-platelet agents aspirin and fish oil, either alone or in combination, will effectively reduce the risk of early thrombosis (blood clots) in arterio-venous fistulae (AVF) that are used for accessing the circulatory system in dialysis. The trial is to be conducted by the Australasian Kidney Trials Network (AKTN). 1200 patients requiring haemodialysis who are scheduled to undergo creation of an AVF and are not cur ....This randomised, placebo-controlled clinical trial aims to determine whether the anti-platelet agents aspirin and fish oil, either alone or in combination, will effectively reduce the risk of early thrombosis (blood clots) in arterio-venous fistulae (AVF) that are used for accessing the circulatory system in dialysis. The trial is to be conducted by the Australasian Kidney Trials Network (AKTN). 1200 patients requiring haemodialysis who are scheduled to undergo creation of an AVF and are not currently taking anti-platelet agents will be recruited over 3 years. AVF is the accepted standard for haemodialysis patients because it utilises the patient's own artery and vein to allow repeated access to the vascular system with a minimal risk of complications. Failure of the AVF means the use of inferior permanent venous catheters or arterio-venous artificial grafts. These devices are more costly to insert, and have an increased risk of failure due to infection and thrombosis. Reducing this rate of failure by simple, cheap and readily available interventions has the potential to reduce these problems. Aspirin has been chosen because of its well-established anti-thrombosis effects. Fish oil has a number of biological effects which make it an attractive agent for the prevention of vascular access thrombosis. Study treatment will be aspirin 100 mg per day or matching placebo, and fish oil 4 gm daily or matching placebo, both commencing on the day prior to surgery and continued for 3 months. If the trial demonstrates a positive effect of either or both agents, this will lead to a reduction in thromboses, quicker time to working dialysis access, and less need for surgery.Read moreRead less
Identifying The Relationship Between Biochemical Markers And Healing In Chronic Leg Ulcers Treated With Compression
Funder
National Health and Medical Research Council
Funding Amount
$374,159.00
Summary
Chronic leg ulcers are a significant cause of pain, immobility and decreased quality of life for 1 - 3% of the over 60 years age group. The condition is difficult to heal and commonly becomes a long term problem, costing the Australian health care system over $500 million - year. Additional costs to the community include loss of productivity and social support systems necessary for people with limited mobility. As the number of people aged over 65 years is expected to double in the next few deca ....Chronic leg ulcers are a significant cause of pain, immobility and decreased quality of life for 1 - 3% of the over 60 years age group. The condition is difficult to heal and commonly becomes a long term problem, costing the Australian health care system over $500 million - year. Additional costs to the community include loss of productivity and social support systems necessary for people with limited mobility. As the number of people aged over 65 years is expected to double in the next few decades, this problem will become increasingly significant. Most chronic leg ulcers are caused by venous disease, and compression bandage therapy is the accepted standard treatment. However, there is little information available on the cellular responses associated with compression treatment and how they promote wound healing. The project proposed here will examine the cellular responses to compression and investigate the relationships between these cellular responses and wound healing. Knowledge gained from the study will provide valuable information for improved techniques to promote wound healing, improved ulcer healing rates, informed decisions on wound care treatment, improved qualtiy of life and reduced health care costs.Read moreRead less
IMPROVE-CKD Study: Impact Of A Phosphate Binder On Cardiovascular Disease In Chronic Kidney Disease.
Funder
National Health and Medical Research Council
Funding Amount
$1,596,698.00
Summary
Chronic kidney disease (CKD) is a significant health problem and is associated with an increased risk of cardiovascular (CV) disease. Vascular calcification and arterial stiffness (stiffening of the blood vessels and arteries) are very common in people with CKD, and are linked to increased death from CV events. This study aims to examine the ways in which treatment with a phosphate binder, Lanthanum Carbonate, may reduce vascular calcification and arterial stiffness to decrease CV events.
Preventing Recurrence Of Leg Ulcers In Older Adults With Peripheral Vascular Disease: Identifying Predictors And Evaluating Strategies.
Funder
National Health and Medical Research Council
Funding Amount
$311,860.00
Summary
Peripheral vascular disease – disease of the arteries and veins in the limbs – leads to chronic leg ulcers for 1–4% of adults aged over 60. The ulcers are slow and difficult to heal and after healing, up to 70% recur, many within a few weeks. The aim of this research is to identify predictors and evaluate strategies to prevent recurrence of chronic leg ulcers; and improve our understanding of relationships between biology, localised disease and health in adults suffering from chronic leg ulcers.
A Case Control Study Of Hypertension In The Setting Of Poverty, Overcrowding And Infection.
Funder
National Health and Medical Research Council
Funding Amount
$603,331.00
Summary
It is unclear why chronic diseases are emerging in regions of significant disadvantage, i.e. where people are not overweight, are physically active and relatively young. We aim to identify factors responsible for the development of high blood pressure in a region where there is overcrowding, poverty, and infection. Low cost strategies to modify risk and educate the community can then be developed to prevent the emergence of these diseases.
The Relationship Between Vascular Remodelling And Mast Cells In Chronic Asthma
Funder
National Health and Medical Research Council
Funding Amount
$353,253.00
Summary
It is known that the airwalls of asthmatics have increased numbers of small blood vessels which can contribute to poor lung function in asthma. The proposed research uses a novel sheep model for chronic asthma to investigate the progressive changes to the blood vessels in the airway walls of asthmatic lungs. The information gained from our sheep model will assist the understanding of blood vessel growth and thus ulitmately help in devising new strategies to treat the effects of asthma.
Assessment Of Bilateral Oedema By Bioelectrical Impedance Analysis
Funder
National Health and Medical Research Council
Funding Amount
$180,000.00
Summary
Swelling of tissue due to fluid accumulation, known as oedema, is one of the earliest signs of diseases such as kidney failure, burn injury or lymphedema. All of these are not uncommon conditions. Lymphedema, for example, is a common sequela of radiotherapy or surgery in the treatment of malignancies such as breast, uterine, and prostatic carcinoma. It is reported to occur in up to 40% of patients depending on the type of surgery and whether or not the patient received radiotherapy. It is estima ....Swelling of tissue due to fluid accumulation, known as oedema, is one of the earliest signs of diseases such as kidney failure, burn injury or lymphedema. All of these are not uncommon conditions. Lymphedema, for example, is a common sequela of radiotherapy or surgery in the treatment of malignancies such as breast, uterine, and prostatic carcinoma. It is reported to occur in up to 40% of patients depending on the type of surgery and whether or not the patient received radiotherapy. It is estimated that at any time 100000 women are suffering from post- mastectomy lymphedema in Australia alone. Treatment of breast cancer alone therefore, given the incidence of the disease, produces a large at-risk population. Add to this other causes of oedema and the magnitude of the problem becomes clearly apparent. The presence of chronic oedema is often a disfiguring and disabling disorder, usually accompanied by pain, recurrent infection, reduced mobility and impaired function. In acute oedema the problem often resolves with recovery from the underlying pathology. In chronic oedema, progression may be arrested by early intervention including complex physical therapy (exercise regimen, compression bandaging, and massage) which is effective in reducing limb volume, in improving the quality of life, function and body image of patients. Although the assessment of oedema is clearly of clinical importance, relatively few objective and accurate techniques for its measurement exist. Research conducted over the past decade by the applicants has pioneered the Use of Bioelectrical Impedance Analysis for the assessment of lymphedema. This study aims to translate this basic research into clinical practice. Sensitivity and specificity studies will establish normative and threshold values for impedance measurements that can be used as presumptive indicators of oedema. User friendly technology and equipment suitable for clinical use will be developed which should improve treatment therapies.Read moreRead less
Characterisation Of MiRNAs That Regulate Vascular Leakage.
Funder
National Health and Medical Research Council
Funding Amount
$167,493.00
Summary
Vascular permeability or leak is a major problem in diseases such as cancer and in cardiovascular diseases . MicroRNAs (miRNAs) are small control genes that influence dveleopment and disease. We have identified a miRNA cluster in endothelial cells, the cells that line the blood vessels, that is important in the control of vascular leak. This project is focused on understanding the impact of these miRNAs in disease.