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MRNA Surveillance In Human Disease: Molecular Determinants Of Nonsense-mediated MRNA Decay
Funder
National Health and Medical Research Council
Funding Amount
$474,517.00
Summary
Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types o ....Inherited diseases are a common cause of human disability, illness and suffering. It has been estimated that 5-10% of the population will be affected by disorders with a genetic component. Thus studies on mechanisms of inherited diseases, especially those relating to genetic mechanisms with relevance across a wide range of individual disorders and gene mutations, are of great significance in diagnosis, molecular pathology and the eventual development of therapeutics. While there are many types of mutations, one relatively common type is called a premature termination mutation. Premature termination mutations introduce an inappropriate genetic signal that tells the cells to stop the formation of proteins before they are complete. This would result in the production of a protein that is shorter than normal, and these short proteins could be quite abnormal and drastically affect the normal function of cells. To overcome this, cells have developed elegant strategies that involve the deployment of quality control, or surveillance, mechanisms to remove the mutant gene product before it can be converted into an abnormal protein. This process is called nonsense mediated decay. Nonsense mediated decay is a complex process and some of the key components have been identified by studies on a small number of genes. However, our studies have identified several previously unknown aspects of the process that suggest that the currently held view of how nonsense mediated decay works is only the beginning of the story and further important complexity exists. The proposed research will explore the basic mechanisms of the surveillance process and determine the signals that initiate nonsense mediated decay. Since premature termination mutations cause one-third of all inherited genetic disorders, our studies will provide new insights into the surveillance mechanisms and will have wide applicability to our understanding of the basis of inherited disease.Read moreRead less
Assembly Of Mitochondrial Respiratory Chain Complexes And Defects Associated With Disease
Funder
National Health and Medical Research Council
Funding Amount
$464,610.00
Summary
A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with ....A group of protein assemblies termed respiratory complexes are found in the inner membrane of mitochondria in our cells and are responsible for producing most of our energy. These complexes consist of many different protein subunits and are built by the help of numerous known and unknown assembly factors. For example, assembly of Complex I of the respiratory chain requires 39 different proteins that are made outside mitochondria and are then transported inside to be somehow joined together with the 7 other subunits that are made by mitochondria. This is clearly a complicated procedure and we have little information on how its assembly is achieved. We do know however that mistakes in the assembly of these complexes (particularly Complex I) do happen. In Australia, about 50 children born each year have inherited disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others present later causing a range of degenerative diseases, particularly affecting brain, muscle and heart. Defects in the respiratory chain have also been implicated in Parkinson's disease, Alzheimer's disease, type-2 diabetes and in cell death. In order to understand how respiratory complex defects cause disease, we need to understand more about how these complexes are built. The aim of this proposal is to investigate how Complex I is assembled, how it interacts with other respiratory complexes, and to identify and characterise proteins that aid in its assembly. We will also analyse assembly defects in cells from patients with suspected respiratory complex deficiencies. This work will aid in our understanding of not only how protein complexes are built, but how defects in their assembly can cause disease. This will be informative to families of affected individuals and may aid in future diagnosis and prevention of diseases where defects in mitochondria are implicated.Read moreRead less
Active Transport Of Calcium Across Dental Enamel Cells - Testing A New Paradigm
Funder
National Health and Medical Research Council
Funding Amount
$258,000.00
Summary
Dental enamel defects and tooth loss affect over half our population, resulting in substantial suffering and economic costs. It is likely that many enamel defects could be prevented, and replacement teeth made more lifelike, if more was known about the cells responsible for producing enamel. A particular problem is our lack of understanding about how enamel-forming cells avoid overdosing on calcium, which can lead to cellular toxicity. The overall aim of this research is to use the latest cell b ....Dental enamel defects and tooth loss affect over half our population, resulting in substantial suffering and economic costs. It is likely that many enamel defects could be prevented, and replacement teeth made more lifelike, if more was known about the cells responsible for producing enamel. A particular problem is our lack of understanding about how enamel-forming cells avoid overdosing on calcium, which can lead to cellular toxicity. The overall aim of this research is to use the latest cell biology and biochemical techniques to elucidate the mechanisms of calcium handling in enamel cells, with developing teeth from rat as the experimental model. Our focus is on calcium transport mechanisms, a field where past theories were overturned by our recent findings with gene-knockout animals. We will test a new theory that has arisen from our investigations, using drugs and gene-silencing techniques to interfere with the cellular machinery now thought to be crucial for transporting calcium. By providing strong physiological evidence for this new mechanism, our expected results will define specific proteins that might be targeted by drugs and nutrition, and provide important information about how dietary fluoride and caffeine affect enamel quality. These findings would change thinking about how enamel defects can be prevented and provide a solid foundation to the exciting new field of dental bioengineering, whose goal is to coax stem cells to make natural replacement teeth.Read moreRead less
Deciphering The Molecular Basis Of SM Regulation Of Exocytosis
Funder
National Health and Medical Research Council
Funding Amount
$515,564.00
Summary
Diabetes, obesity, heart disease and physical inactivity are major and escalating health problems within western societies. These problems are all linked to, or aggravate, the condition known as insulin resistance. Insulin resistance occurs when normal levels of insulin are insufficient to remove glucose from the blood. In the normal situation, insulin regulates glucose uptake into muscle and fat cells by stimulating the movement of a glucose transport protein from inside the cell to the cell su ....Diabetes, obesity, heart disease and physical inactivity are major and escalating health problems within western societies. These problems are all linked to, or aggravate, the condition known as insulin resistance. Insulin resistance occurs when normal levels of insulin are insufficient to remove glucose from the blood. In the normal situation, insulin regulates glucose uptake into muscle and fat cells by stimulating the movement of a glucose transport protein from inside the cell to the cell surface. The trafficking of this protein is somehow disrupted in insulin resistance. The purpose of this research is to follow up our exciting preliminary results on this system to shed light on the molecular processes that regulate the trafficking of the glucose transporter. Information resulting from our studies will lead to a better understanding of insulin-stimulated glucose transport and may also unravel the details of a related cellular secretion system that regulates neurotransmission. Our hope is that by understanding at the molecular level how cells regulate secretion, we can in the future develop therapeutics to counteract many of today s major health problems.Read moreRead less
Mechanisms Of Nedd4/Nedd4-2-mediated Regulation Of The Epithelial Sodium Channel
Funder
National Health and Medical Research Council
Funding Amount
$471,000.00
Summary
The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Abnormal regulation of ENaC is associated with conditions such as hypertension, cystic fibrosis and pulmonary oedema. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease me ....The epithelial sodium channel (ENaC) is a highly specific ion channel expressed in the apical membrane of some tissues. In the kidney, ENaC activity is responsible for maintaining sodium balance, blood volume and blood pressure. In the lung ENaC function is required for fluid clearance. Abnormal regulation of ENaC is associated with conditions such as hypertension, cystic fibrosis and pulmonary oedema. Delineating the molecular basis of the regulation of ENaC is vital in understanding disease mechanisms and in defining targets for novel therapeutics for the treatment of disorders that arise due to sodium imbalance. Furthermore, ENaC and the molecules involved in the channel regulatory cascade are potential candidate genes in defining the genetic causes of human hypertension and salt wasting disorders. Previous studies from our laboratories and by other groups have shown that Nedd4 and Nedd4-2 proteins are key players in regulating ENaC activity. Our recent NHMRC supported work has identified another important protein, Grk2, as a regulator of ENaC. The work proposed in this application is an extension of our recent findings and will enable us to fully define how Nedd4-Nedd4-2 and Grk2 regulate the activity of ENaC.Read moreRead less
The design of targetable epigenetic modifiers. The project aims to engineer enzymes as valuable tools for understanding gene expression mechanisms and potentially a technology for altering gene expression in plants, animals or humans in a targetable manner. The genetic information encoded in the DNA of all complex organisms has been shown to be augmented by decorations on both DNA and the histone proteins that package DNA. This so-called epigenetic information is important but not well understoo ....The design of targetable epigenetic modifiers. The project aims to engineer enzymes as valuable tools for understanding gene expression mechanisms and potentially a technology for altering gene expression in plants, animals or humans in a targetable manner. The genetic information encoded in the DNA of all complex organisms has been shown to be augmented by decorations on both DNA and the histone proteins that package DNA. This so-called epigenetic information is important but not well understood. The project plans to design highly specific and targetable enzymes that can interrogate and manipulate epigenetic information in living cells. Understanding the regulation of gene expression and controlling the expression of chosen genes may form a foundation for applications in agriculture, biology and medicine.Read moreRead less
The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via ....The insulin-like growth factor system is involved in promoting cancer growth and survival against treatment with chemotherapy. Insulin-like growth factors-I and -II act via cell surface receptors (IGF-1R). Much effort has been applied to blocking the action of insulin-like growth factors via IGF-1R. However, recently a second mechanism has been identified by which the insulin-like growth factors are involved in cancer. Insulin-like growth factor-II can also promote cancer growth and survival via an alternative form of the insulin receptor. We will join with our international collaborator to bring together a team of biochemists and protein structural biologists who are world leaders in understanding protein interactions in the insulin and insulin-like growth factor systems. As relatively little is known about this alternate pathway we propose to define the mechanism of binding of insulin-like growth factor-II to the alternate insulin receptor isoform. Using a combination of well-established and novel techniques we will map the interaction. This knowledge will allow design of specific inhibitors to block the action of insulin-like growth factor-II in promotion of cancer cell growth and survival without disruption of the metabolic actions of the insulin receptor.Read moreRead less
Exploring the catalytic role of the Rubisco small subunit: a new target for improving carbon dioxide-fixation in plants. This project uses new biotechnological tools to improve the performance of the photosynthetic protein Rubisco, the primary carbon dioxide-fixing enzyme in plants. By supercharging photosynthesis, this research will help to boost yield and reduce water and nitrogen use in crops.
Rubisco for all climates: unlocking the enzyme's structure-function relations for more efficient photosynthesis. This projects biotechnological research will identify structural features in the carbon dioxide (CO2)-capturing enzyme from plants that improve its performance, particularly at warmer temperatures. This knowledge is vital for predicting the influence of climate change on crop productivity and paving the way for supercharging photosynthesis to boost crop performance.