Characterisation Of Novel AGE Binding Proteins: Implications For Diabetic Vascular Complications.
Funder
National Health and Medical Research Council
Funding Amount
$210,990.00
Summary
This project will explore a process known as advanced glycation and in particular how this may lead to organ injury in diabetes. Diabetes is characterised by sustained elevation of blood glucose levels which interact with proteins to generate products known as advanced glycation end-products (AGEs). These AGEs bind to other proteins some of which have been isolated and are considered receptors. Our own group has identified a new family of proteins known as ERM proteins which bind to AGEs. This i ....This project will explore a process known as advanced glycation and in particular how this may lead to organ injury in diabetes. Diabetes is characterised by sustained elevation of blood glucose levels which interact with proteins to generate products known as advanced glycation end-products (AGEs). These AGEs bind to other proteins some of which have been isolated and are considered receptors. Our own group has identified a new family of proteins known as ERM proteins which bind to AGEs. This is a highly novel finding which now needs to be examined in more detail. The ERM proteins which include ezrin, radixin and moiesin are found at many sites of diabetic complications including the kidney, retina and blood vessel wall. They have a number of functions including effects on cell adhesion and cell structure. This is important in diabetes where changes in cells including altered structure have been observed. This grant will characterise the interactions between AGEs and ERM proteins at the molecular and cellular level. It will define how AGEs influence cells via interactions with ERM proteins. These studies have the potential to lead to treatments that may modulate the AGE-ERM interactions, thereby retarding or preventing diabetic vascular complications. These complications are of important clinical significance since they are the major cause of morbidity and mortality in the diabetic population. Furthermore, diabetes is a major cause of premature atherosclerosis in our community, diabetic kidney disease is the leading cause of end-stage renal failure in the Western world and diabetic retinopathy (eye disease) is the main cause of blindness in the working age population.Read moreRead less
Cytosolic Oxidative Disturbances As A Source Of Mitochondrial Dysfunction In Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$505,786.00
Summary
There is a critical need to identify new therapies for the growing number of patients with diabetic kidney disease. Current medicines only retard progressive disease. Our studies investigate defects in the power houses of the cell, the mitochondria. These defects cause generation of toxic free oxygen radicals which eventually starve the cell of energy production. Therefore, reversal of mitochondrial defects in diabetic kidney disease may be a novel therapeutic target.
Role Of The Podocyte In Diabetic Nephropathy: Structural, Functional, Molecular And Interventional Studies
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
Kidney disease is a major cause of disability and premature death in the Australian population. In disease the kidney's ability to filter out impurities and toxins in blood is impaired as a consequence of excessive cell growth and scar tissue formation. Studies from our group indicate that a highly specialised cell within the kidney's filtering apparatus becomes altered early in the course of diabetes. In the setting of diabetes, this cell, called the podocyte, stretches and begins forming scar ....Kidney disease is a major cause of disability and premature death in the Australian population. In disease the kidney's ability to filter out impurities and toxins in blood is impaired as a consequence of excessive cell growth and scar tissue formation. Studies from our group indicate that a highly specialised cell within the kidney's filtering apparatus becomes altered early in the course of diabetes. In the setting of diabetes, this cell, called the podocyte, stretches and begins forming scar tissue. In addition, it no longer maintains its barrier function and starts to leak protein. The proposed studies will explore the mechanisms that lead to these diabetes-induced changes in the podocyte. In addition, strategies for reversing these changes will also be explored in detail with the aim of providing new treatments for diabetic kidney disease.Read moreRead less
NOX Isoforms In Diabetes Associated Vascular Injury: Implications For Therapeutic Strategies
Funder
National Health and Medical Research Council
Funding Amount
$441,511.00
Summary
These studies will investigate the role of oxidative stress and enzymes involved in oxidative stress production in diabetes associated blood vessel injury and kidney damage, leading to heart attacks, stroke and kidney failure. We will use unique knockout animal models and novel drug treatments. Ultimately, we aim to develop novel treatments to better treat and prevent diabetes related complications.
Kidney failure is a devastating consequence of diabetes mellitus. Evidence exists that increased amounts of glucose are filtered by the kidney and then together with salt is reaborbed, in patients with diabetes. The increased glucose and salt reabsorption is considered to trigger cellular damage leading to renal failure. The studies will determine if reducing glucose and salt resportion by the kidney protects against the development of renal failure in models of diabetic renal disease.
NOVEL REGULATORS OF CONNECTIVE TISSUE GROWTH FACTOR EXPRESSION AND BIOACTIVITY IN DIABETIC COMPLICATIONS
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Diabetes mellitus is common in our community. It causes much premature death and loss of quality of life. Recent data from Australian studies show that ~7% of adults over 25 years, and ~20% of people aged over 65 have diabetes, and diabetes in both children and adults is increasing in Australia. A critical problem caused by diabetes, irrespective of its cause, is that blood glucose levels are higher than normal. High blood glucose contributes to much of the damage to body tissues and to the earl ....Diabetes mellitus is common in our community. It causes much premature death and loss of quality of life. Recent data from Australian studies show that ~7% of adults over 25 years, and ~20% of people aged over 65 have diabetes, and diabetes in both children and adults is increasing in Australia. A critical problem caused by diabetes, irrespective of its cause, is that blood glucose levels are higher than normal. High blood glucose contributes to much of the damage to body tissues and to the early death that can occur in diabetes. Unfortunately, given our current treatment methods, in only a small number of patients can glucose levels in the body be consistently controlled into the normal range. How does high blood glucose cause damage to the body and its different tissues? This is a complex process. One way that damage occurs is through an increase in some of the growth factors in the body. In diabetes, high blood glucose can increase the production of some growth factors in an uncontrolled way. In turn, these growth factors then cause tissue damage. One of the growth factors that can be increased by the high glucose in diabetes is called connective tissue growth factor, or CTGF. CTGF can cause scars to form in tissues, and it is increased in diabetes in humans. Through NHMRC sponsored post-doctoral research over the past four years, Dr Twigg has published findings showing pathways by which diabetes causes increases in CTGF, and ways in which CTGF then causes tissue scarring. The current grant proposal presents new data showing further novel pathways by which CTGF is activated by diabetes and ways in which CTGF causes scarring. The pathways involved will be studied in detail in the project. In addition, methods to block CTGF and its harmful effects in diabetes will be developed in this work. By controlling CTGF, it is envisaged that damage to tissues will be reduced, leading to improved quality and quantity of life for people who have diabetes.Read moreRead less
Role Of Vasoactive Hormones And Cytokines In Diabetic Nephropathy
Funder
National Health and Medical Research Council
Funding Amount
$361,650.00
Summary
Kidney disease is a major cause of disability and premature death in the Australian population. In diabetic kidney disease a major factor which accelerates the progression of this disorder is the presence of hypertension. Indeed international and national organisations now recommend aggressive blood pressure treatment in the diabetic patient. This proposal aims to optimise blood pressure treatment in diabetes and evaluate novel more potent blood pressure lowering agents which block within the ki ....Kidney disease is a major cause of disability and premature death in the Australian population. In diabetic kidney disease a major factor which accelerates the progression of this disorder is the presence of hypertension. Indeed international and national organisations now recommend aggressive blood pressure treatment in the diabetic patient. This proposal aims to optimise blood pressure treatment in diabetes and evaluate novel more potent blood pressure lowering agents which block within the kidney important hormonal pathways implicated in diabetic kidney disease. This approach will assist in determining key factors which mediate the damage to the kidney induced by elevated blood pressure. It is anticipated that these studies will lead to more rational, targeted and powerful antihypertensive agents which will retard or prevent the development of diabetic nephropathy.Read moreRead less
Role Of Growth And Transcription Factors In Tubulointerstitial Injury In Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$454,023.00
Summary
Progressive kidney disease occurs as a result of a range of molecular and cellular pathways. One of the commonest causes of kidney disease is diabetes and this appears to be partly related to increased expression and action of certain growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney and one of the ways these promote this scarring is to change a cell s behaviour so that it now lays down collagen. This proposal will not only focus on how CTGF promotes ....Progressive kidney disease occurs as a result of a range of molecular and cellular pathways. One of the commonest causes of kidney disease is diabetes and this appears to be partly related to increased expression and action of certain growth factors such as CTGF. These factors promote the deposition of scar tissue in the kidney and one of the ways these promote this scarring is to change a cell s behaviour so that it now lays down collagen. This proposal will not only focus on how CTGF promotes scarring but will explore 2 novel factors called Snail and Slug which can act directly on particular genes such as CTGF to inhibit these deleterious effects. By further characterising these pathways involving Snail, Slug and CTGF in the kidney it will be possible to generate new targets and therapies for various forms of progressive kidney disease including diabetic kidney disease.Read moreRead less
The Role Of Angiotensin Converting Enzyme 2 In Diabetic Complications
Funder
National Health and Medical Research Council
Funding Amount
$453,144.00
Summary
Most heart attacks and strokes arise from narrowing of the arteries. This process is regulated by a number of hormonal pathways. One of the most important is the renin angiotensin system. Our group has demonstrated important changes in this pathway which play a pivotal role in regulating the development of atherosclerosis and its response to treatment. It is predicted that these studies will provide critical information to develop innovative treatment strategies for cardiovascular disease.
Progressive Renal And Vascular Disease: Pivotal Role Of The AT2 Receptor
Funder
National Health and Medical Research Council
Funding Amount
$283,875.00
Summary
Diabetes and renal disease are commonly associated with a range of vascular complications. I have been investigating a particular hormone system known as the renin-angiotensin system in promoting kidney and vascular complications in various diseases including diabetes. This system is a pathway which ultimately generates a hormone called angiotensin II which has many actions which could be harmful to the kidney and blood vessels. The importance of this hormone system has been demonstrated by the ....Diabetes and renal disease are commonly associated with a range of vascular complications. I have been investigating a particular hormone system known as the renin-angiotensin system in promoting kidney and vascular complications in various diseases including diabetes. This system is a pathway which ultimately generates a hormone called angiotensin II which has many actions which could be harmful to the kidney and blood vessels. The importance of this hormone system has been demonstrated by the beneficial effects particularly on the kidney of drugs which block this pathway. It has been demonstrated that angiotensin II acts via 2 different receptors, the AT1 and AT2 subtypes. Initially the AT1 receptor was viewed to mediate most of the biological effects of angiotensin II. However, as demonstrated by our own and other groups, the AT2 receptor may play a role in mediating various effects of angiotensin II particularly in disease states. We have identified expression of this receptor in the adult kidney and in the vessel wall which may be upregulated in various disease states. The status of the AT2 receptor is not well characterised in diabetes and many other kidney diseases and this proposal will address this issue in a comprehensive manner by evaluating various sites of injury in diabetes including the kidney and vascular tree. This proporsal includes different approach to moduate this receptor involving drug blockers and animal model where this receptoris either deleted or overexpressed. These studies potentially have major implications for the management of diabetic and renal complications. It remains to be determined if the AT2 receptor confers beneficial or deleterious effects in diabetic nephropathy or other renal diseases, if these effects vary among the various organs to be studied and whether AT2 receptor antagonists may themselves be of therapeutic value in individuals at high risk of kidney and vascular disease such as people with diabetes.Read moreRead less