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
A NEW LOOK AT THE ROLE(S) OF GLYCOGEN AND SUGAR PHOSPHATES IN SKELETAL MUSCLE CONTRACTILITY
Funder
National Health and Medical Research Council
Funding Amount
$193,224.00
Summary
According to textbooks, glycogen in skeletal muscle is a homogenous molecular species whose sole role in muscle contraction is that of a carbohydrate-energy store. Likewise, sugar phosphates, such as glucose1-phosphate (G1-P), glucose 6-phosphate (G6-P), fructose 6-phosphate (F6-P) and fructose 1,6-bisphosphate (F1,6-bP) are generally presented as negatively charged compounds that act only as substrates-products of intermediary reactions in sugar degradation pathways. However, there is now compe ....According to textbooks, glycogen in skeletal muscle is a homogenous molecular species whose sole role in muscle contraction is that of a carbohydrate-energy store. Likewise, sugar phosphates, such as glucose1-phosphate (G1-P), glucose 6-phosphate (G6-P), fructose 6-phosphate (F6-P) and fructose 1,6-bisphosphate (F1,6-bP) are generally presented as negatively charged compounds that act only as substrates-products of intermediary reactions in sugar degradation pathways. However, there is now compelling evidence that (i) glycogen depletion impairs muscle contractility even when there is no shortage of cellular energy, (ii) there are two molecular forms of glycogen, and (iii) sugar phosphates can act as potent modifiers of functional domains in muscle proteins. This project addresses a number of novel questions regarding the role (s) of glycogen and sugar phosphates in muscle contractility and the cellular mechanisms involved. The knowledge produced will further our understanding of the correlation between Excitation-Contraction coupling and different intracellular glycogen pools, and of the molecular basis of prolonged effects of sugar phosphates on the contractile machinery. Furthermore, this work should also generate valuable insights into complex physiological (e.g. fatigue and aging) and pathological (e.g. atherosclerosis, metabolic myopathies) conditions which are still poorly understood.Read moreRead less
Evaluation And Comparison Of Lentiviral And AAV Vector Mediated Gene Therapy For The Mucopolysaccharidoses
Funder
National Health and Medical Research Council
Funding Amount
$521,320.00
Summary
The mucopolysaccharidoses are a group of inherited diseases that have profound consequences for affected individuals. They have pleiotropic effects and usually result in premature death. Although intravenous enzyme replacement therapy has been developed for a number of these disorders, this approach to therapy is invasive, very expensive, of limited efficacy, and is completely ineffective in treating brain pathology. The principal reason for this is the protected nature of the brain which preven ....The mucopolysaccharidoses are a group of inherited diseases that have profound consequences for affected individuals. They have pleiotropic effects and usually result in premature death. Although intravenous enzyme replacement therapy has been developed for a number of these disorders, this approach to therapy is invasive, very expensive, of limited efficacy, and is completely ineffective in treating brain pathology. The principal reason for this is the protected nature of the brain which prevents enzymes that are administered intravenously from entering. Therefore, alternative therapies must be considered in order to provide more effective therapy for the mucopolysaccharidoses, especially those that have significant brain pathology. Gene therapy is one such alternative therapy but this still faces the problem of introducing the therapeutic agent (in this case the gene encoding the requisite enzyme) into the brain. This project aims to provide a comparitive evaluation of two gene therapy vectors for their efficacy in treating all aspects of the pathology found in the mucopolysaccharidoses. Both vectors have the properties of being able to efficiently deliver genes to different cell types and result in the stable genetic modification of the target cell, making them ideal for long-term treatment. However, for effective gene therapy, significant and widely distributed gene delivery to the brain, as well as to other tissues, will be required. This project aims to compare the efficacy of these vectors in two different animal models of the mucopolysaccharidoses that exhibit a wide range of the clinical problems associated with these diseases, importantly including brain pathology.Read moreRead less
Studies Of A Novel Manganese Transporter In Lysosomes And Its Implications In Niemann-Pick Type-C Disease
Funder
National Health and Medical Research Council
Funding Amount
$527,036.00
Summary
Niemann-Pick type-C disease is a devastating disease affecting child central nervous system. It is due to too much build up of cholesterol in the lysosomal compartment of cells. Recent studies indicate that bivalent cations are involved in the development of the disease. We recently discovered a manganese transporter in the lysosomal compartment and its interaction of the a protein that causing the disease. We will elucidate how manganese transporter controls trace metal balance and may prevent ....Niemann-Pick type-C disease is a devastating disease affecting child central nervous system. It is due to too much build up of cholesterol in the lysosomal compartment of cells. Recent studies indicate that bivalent cations are involved in the development of the disease. We recently discovered a manganese transporter in the lysosomal compartment and its interaction of the a protein that causing the disease. We will elucidate how manganese transporter controls trace metal balance and may prevent the disease.Read moreRead less