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Understanding The Importance Of Lipid Metabolism In Mediating The Anti-diabetic Effects Of Metformin
Funder
National Health and Medical Research Council
Funding Amount
$555,892.00
Summary
Obesity is a major cause of adult onset Type 2 diabetes. This project is investigating the mechanism of action of the glucose lowering drug metformin on fat metabolism. We are investigating whether the regulation of two enzymes, involve in fat synthesis and the burning of fat respectively that are important for metformin�s action. Through this research we hope to improve on the treatment of Type 2 diabetes and cardiovascular disease.
Physiological Effects Of Manipulating AMP-activated Kinase Genes
Funder
National Health and Medical Research Council
Funding Amount
$351,110.00
Summary
The AMP-activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During vigorous exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and stimulates glucose uptake and burning of fat to provide energy. The AMP-activated protein kinase also regulates the production of nitric oxide that is important in controlling blood pressure and blood clotting. Reduced caloric intake activates ....The AMP-activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During vigorous exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and stimulates glucose uptake and burning of fat to provide energy. The AMP-activated protein kinase also regulates the production of nitric oxide that is important in controlling blood pressure and blood clotting. Reduced caloric intake activates the AMP-activated protein kinase to suppress energy consuming activities and modify the expression of genes. Many of the conditions that activate the AMP-activated protein kinase (exercise, reduced caloric intake) are associated with a healthy life style, increased longevity and resistance to age onset diseases including cardiovascular disease (atherosclerosis, hypertension), obesity, neurodegeneration and diabetes. By manipulating the gene for the AMP-activated protein kinase in mice we expect to learn more about its key physiological roles and give new insight into the control of age onset diseases.Read moreRead less
AMP-activated Protein Kinase (AMPK) In Acute Renal Failure
Funder
National Health and Medical Research Council
Funding Amount
$401,523.00
Summary
Acute renal failure is a common complication of any severe illness. Generally, it is the lack of blood flow, or food that leads to this problem. People who are ill are unable to provide adequate blood flow to their kidneys, so the kidneys become diseased and fail to function. This can be fatal. There are, however, mechanisms in the kidney that are designed to avoid this shortage of energy. The aim of these studies is to find out what these protective mechanisms usually do in the kidney, and unde ....Acute renal failure is a common complication of any severe illness. Generally, it is the lack of blood flow, or food that leads to this problem. People who are ill are unable to provide adequate blood flow to their kidneys, so the kidneys become diseased and fail to function. This can be fatal. There are, however, mechanisms in the kidney that are designed to avoid this shortage of energy. The aim of these studies is to find out what these protective mechanisms usually do in the kidney, and understand why they are not more active. We hope to find ways to switch them on earleir, using drugs, so as to protect the kidneys from injury.Read moreRead less
Adiponectin: Key Factors Determining Its Metabolic Actions And Influences On Insulin Sensitivity
Funder
National Health and Medical Research Council
Funding Amount
$604,793.00
Summary
Diabetes and obesity are growing at alarming rates due to poor lifestyle and other factors. Adiponectin is a complex molecule secreted by fat tissue that may help to burn fat in other tissues such as muscle and liver. We investigate what are the main determinants of adiponectin action and how these might counteract defective insulin action caused by excessive fat intake. This promises to provide new therapeutic targets to lessen the metabolic derangement associated with diabetes and obesity
Protein Kinases Regulate Salt Reabsorption In The Kidney
Funder
National Health and Medical Research Council
Funding Amount
$531,696.00
Summary
This proposal is designed to determine how the kidney senses the level of salt in the body and monitors blood pressure. This is critical for diseases such as hypertension, kidney and heart failure, where salt is retained inappropriately. We propose that the kidney uses proteins called kinases that are activated by salt in the kidney. When it is too low, they detect this and cause the kidney to absorb more salt to correct the deficiency. The way that they are able to do this has profound implicat ....This proposal is designed to determine how the kidney senses the level of salt in the body and monitors blood pressure. This is critical for diseases such as hypertension, kidney and heart failure, where salt is retained inappropriately. We propose that the kidney uses proteins called kinases that are activated by salt in the kidney. When it is too low, they detect this and cause the kidney to absorb more salt to correct the deficiency. The way that they are able to do this has profound implications for human heart and kidney disease, and biology in general.Read moreRead less
Regulation Of The Na-K-Cl Co-transporter By The AMP-activated Protein Kinase
Funder
National Health and Medical Research Council
Funding Amount
$227,036.00
Summary
The failure of the kidney to excrete enough salt is a major driving force behind high blood pressure, kidney failure and heart disease. At present, it is not known, in any detail, how the kidney is able to recognise that it is not excreting enough salt and how it changes the amount it excretes. This is important if, for example, someone eats a salty meal. Unless the kidney recognises that there is an excess of salt and adjusts itself to excrete it, then salt accumulates leading to high blood pre ....The failure of the kidney to excrete enough salt is a major driving force behind high blood pressure, kidney failure and heart disease. At present, it is not known, in any detail, how the kidney is able to recognise that it is not excreting enough salt and how it changes the amount it excretes. This is important if, for example, someone eats a salty meal. Unless the kidney recognises that there is an excess of salt and adjusts itself to excrete it, then salt accumulates leading to high blood pressure, kidney and cardiac problems. In this study, we have identified a new mechanism that the kidney uses to detect salt and to excrete it. This could be a major advance in our understanding of high blood pressure and other common diseases.Read moreRead less
Physiological Effects Of Manipulating AMPK Signalling Genes
Funder
National Health and Medical Research Council
Funding Amount
$377,250.00
Summary
The AMP activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and switches on metabolic processes to restore energy. This includes stimulating glucose uptake and burning fat. With training the AMP activated protein kinase also controls genes to adapt the body to future exercise. Reducing caloric intake activates the A ....The AMP activated protein kinase is a metabolic stress sensing protein kinase responsible for matching the supply of energy to the body's functions. During exercise it senses metabolic stress (reduction in energy) caused by muscle contraction and switches on metabolic processes to restore energy. This includes stimulating glucose uptake and burning fat. With training the AMP activated protein kinase also controls genes to adapt the body to future exercise. Reducing caloric intake activates the AMP activated protein kinase to suppress energy consuming activities and modify the expression of genes. This enzyme is a powerful regulator of lipid metabolism, inhibiting both cholesterol and triglyceride synthesis. Many conditions that activate the AMP activated protein kinase (exercise, reduced caloric intake) are associated with a healthy lifestyle, increased longevity and resistance to age onset diseases including cardiovascular disease (atherosclerosis, hypertension), obesity, neurodegeneration and diabetes. It has been found that metformin and rosiglitizone, major drugs used to treat people with type II diabetes activate the AMP activated protein kinase. By manipulating the genes for the AMP-activated protein kinase in mice we expect to gain new insights into the physiological roles of this enzyme and how it functions to protect the body from age onset diseases.Read moreRead less
REGULATION OF PROTEIN KINASES AND THEIR SUBSTRATES
Funder
National Health and Medical Research Council
Funding Amount
$1,296,159.00
Summary
Protein kinases are important regulatory enzymes involved in the control of virtually all physiological processes at the cellular level. The human genome is thought to contain approximately 1500 protein kinases to control these processes. These enzymes add phosphate groups to target proteins to modify their functions in a reversible manner with protein phosphatases removing the phosphate groups. This project is concerned with studying a metabolic stress sensing protein kinase called the AMP acti ....Protein kinases are important regulatory enzymes involved in the control of virtually all physiological processes at the cellular level. The human genome is thought to contain approximately 1500 protein kinases to control these processes. These enzymes add phosphate groups to target proteins to modify their functions in a reversible manner with protein phosphatases removing the phosphate groups. This project is concerned with studying a metabolic stress sensing protein kinase called the AMP activated protein kinase and its substrates. During periods of high energy demand such as vigorous exercise or nutrient stress induced by starvation or ischaemia the AMP activated protein kinase is responsible for shutting down energy requiring metabolic pathways and accelerating metabolism including glucose uptake and fatty acid metabolism to restore cellular energy levels. The AMP activated protein kinase regulates key enzymes in the control of cholesterol and lipid (fatty acid) synthesis as well as endothelial NO synthase, a key regulator of blood pressure and platelet activity. For these reasons it is potentially important in cardiovascular disease. The AMP activated protein kinase also appears responsible for exercise induced glucose uptake and it is known that exercise helps restore glucose control in age onset or type II diabetic patients. Since the AMP acitivated protein kinase accelerates fatty acid metabolism it may also have a role in obesity. While many factors are thought to be involved in cardiovascular disease, diabetes and obesity the AMP activated protein kinase is a key metabolic regulatory enzyme relevant to the most important diseases in Australia. Understanding the structure and function of the AMP activated protein kinase as well as the genes that encode this enzyme is an important goal.Read moreRead less
An AMPK Myristoyl Switch Controls AMP Mediated Metabolic Stress Signaling
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
This project is investigating an enzyme called AMP-activated protein kinase that plays a pivotal role in controlling how our bodies regulate energy metabolism in response to exercise and diet. Improved understanding of how this enzyme is regulated may provide new therapeutic methods for mimicking the beneficial effects of diet and exercise to treat multiple metabolic diseases including obesity, Type 2 diabetes and cardiovascular disease.
Structure And Function Of The AMPK Glycogen-binding Domain
Funder
National Health and Medical Research Council
Funding Amount
$538,764.00
Summary
The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results i ....The AMP-activated protein kinase (AMPK) is an enzyme responsible for coordinating metabolism in response to energy supply (diet) and energy demand (exercise). Research into this kinase can increase our understanding of how diet and exercise are so important for maintaining health. The kinase acts either by sensing when cellular energy levels become too low for normal functioning or when the body tells it by sending a chemical messenger (hormone) that overall energy levels are low. This results in activation of energy-producing pathways and inhibition of energy-consuming pathways, allowing cells to match supply with demand to ensure their survival. The AMPK comprises of three proteins that together form a functional enzyme. I have previously found that AMPK localizes to a source of cellular energy called glycogen (sugar stores) via one part that I have called the glycogen-binding domain. In this application I aim to obtain a thorough understanding of the molecular basis of how the glycogen-binding domain affects AMPK function in muscle and heart following exercise. In addition this research may lead to the identification of new molecules, similar to glycogen, that are important for AMPK regulation and may lead to the development of a new class of drugs for Type 2 Diabetes. Research into AMPK promises to dramatically increase our knowledge of how to reduce the risk of cardiovascular and neurodegenerative diseases, diabetes and obesity and provide an understanding of the reasons these diseases develop.Read moreRead less