Insulin-like Growth Factor Binding Protein-2 Is A Crucial Activator Of Aggressive Behaviour In Cancer Cells
Funder
National Health and Medical Research Council
Funding Amount
$612,885.00
Summary
The insulin-like growth factor (IGF) system, required for normal development and adult life, is often altered in many diseases including cancer. Key regulators of the IGF system are the IGF binding protein (IGFBP) of which IGFBP-2 is the 2nd most abundant. IGFBP-2 may enhance or inhibit the IGFs, but the mechanisms are not clear. This proposal aims to dissect IGFBP-2 action with the ultimate goal to provide knowledge for the development of targeted therapeutic modulators of IGFBP-2 activity.
Diabetic cardiomyopathy (DiabCM) is common in people with diabetes. It predisposes to heat failure. Its cause remains unclear and there is no specific treatment for DiabCM. Inflammation is a fundamental tissue response to a metabolic insult and it occur in DiabCM. The central hypothesis in this work is that inflammation through myocardial macrophage cells contributes to DiabCM. This hypothesis will be tested in animal models and also in cell culutre studies.
Role And Mechanism Of Connective Tissue Growth Factor In Diabetic Cardiomyopathy
Funder
National Health and Medical Research Council
Funding Amount
$382,820.00
Summary
Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by diabetes. It is being recognised as a prominent cause of both acute and chronic heart failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At present however, no treatments are available to directly treat the cardiomyopathy. This condition can also occur in people with diabetes who have high blood pressure and-or coronary artery disease and may combine with these problems to worsen pa ....Diabetic cardiomyopathy is a condition where the heart muscle is directly damaged by diabetes. It is being recognised as a prominent cause of both acute and chronic heart failure in diabetes. It is common and occurs in up to 60% of diabetic patients . At present however, no treatments are available to directly treat the cardiomyopathy. This condition can also occur in people with diabetes who have high blood pressure and-or coronary artery disease and may combine with these problems to worsen patient outcomes. We have generated data in experimental diabetes in rodents that strongly implicates a heart growth factor in causing diabetic cardiomyopathy. This protein, called connective tissue growth factor (CTGF), is increased in diabetic cardiomyopathy, and is elevated by high glucose and other factors in diabetes. We have published data showing that CTGF causes tissue scarring like that which occurs in cardiomyopathy, by affecting signals in cells called fibroblasts. It increases the laying down of extracellular matrix (ECM) and also inhibits the degradation of ECM by the proteins that break down matrix, known as the MMPand PAI systems. Such accumulation of ECM is thought to be a major factor leading to abnormal muscle function in cardiomyopathy. We now plan to block CTGF in this diabetic heart model to determine if we can prevent diabetic cardiomyopathy. We have generated two methods to inhibit CTGF in the animal model. Echocardiography (a heart ultrasound test), and molecular analysis of the heart tissue will determine if we can prevent the otherwise adverse functional and structural changes of diabetes in the heart. We will also study our baboon model of diabetes to determine if diabetic cardiomyopathy with increased heart CTGF is present in the primates. Cell culture studies from rat heart fibroblasts and myocytes will determine how CTGF has the effect on cells to cause cardiomyopathy and how we might further prevent this condition developing in diabetes.Read moreRead less
Validating A New Model For Growth Hormone Receptor Activation
Funder
National Health and Medical Research Council
Funding Amount
$472,500.00
Summary
Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflam ....Growth hormone is an important hormone therapeutic for treating dwarfism. Recently, many new therapeutic applications for growth hormone have been discovered, particularly in relation to its anabolic actions. These include post surgery recovery, enhanced bone fracture healing, Crohns disease, dilated cardiomyopathy, infertility and ageing. The hormone exerts these actions through its receptor, which is a class1 cytokine receptor, similar to many receptors important in regulating immunity, inflammation, metabolism and cancers. In principle, if we can find out how the GH receptor works, this information would help in designing drugs to treat many immune and inflammatory disorders. With current NHMRC support we have developed a model which describes how GH activates the receptor at a molecular level. The model involves two pre-associated receptors at the cell surface binding to the hormone, with the result that the receptors are rotated relative to each other, and this brings the two JAK2 signalling units attached tothe receptor inside the cell into alignment, so they can activate each other. We can activate the receptor without hormone by artificially rotating it. This model is a prediction based on several techniques, but lacks proof of rotation. There are also a number of issues relating to the need for rigidity in the receptors, so the torque can be transmitted into the cell, since many believe there is no rigidity just above the membrane. We predict there is , but need to prove this. This information is vital for designing small orally active mimics of growth hormone, and for developing GH antagonists, likely to be useful for breast and colon cancer. Finally, we have evidence that the specificity of receptor signalling can be changed by mutating the outer part of the receptor (novel). We believe this can be used to change the activity spectrum of GH, hence decrease side effects, by developing analogs which activate one pathway or the other.Read moreRead less
Non-alcoholic steato-hepatitis (NASH) is a common disease of liver inflammation and scarring, which may progress to cirrhosis or liver cancer. While type 2 diabetes causes a higher rate of NASH and more rapid NASH progression the reasons for this are not clear. We have developed a novel animal model of NASH with diabetes added to dietary induced obesity. We show that a growth factor is elevated in the affected livers. We plan to block the growth factor to see if we can prevent NASH worsening.