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
Structure And Function Of The Alternative Splicing Factor ZNF265
Funder
National Health and Medical Research Council
Funding Amount
$509,017.00
Summary
Now that the human genome has been sequenced, we can see that a human being is defined bye approximately 30000 genes. One of the biggest surprises to come from this work was that the number of genes was significantly smaller than many predicted. Similar surprise was registered at the discovery that the genome of the fruit fly actually contained fewer genes than that of the model worm, Caenorhabditis elegans. Part of the explanation for these apparent discrepencies lies in the phenomenon known as ....Now that the human genome has been sequenced, we can see that a human being is defined bye approximately 30000 genes. One of the biggest surprises to come from this work was that the number of genes was significantly smaller than many predicted. Similar surprise was registered at the discovery that the genome of the fruit fly actually contained fewer genes than that of the model worm, Caenorhabditis elegans. Part of the explanation for these apparent discrepencies lies in the phenomenon known as gene splicing, whereby one gene can actually give rise to many different isoforms of the same protein. These different isoforms can have different structures and-or functions, and dramatically increase the complexity that it is possible for an organism to achieve with a given number of genes. The process of splicing is very intricate, requiring precise control to allow an organism to develop normally. Many human genetic diseases are known to arise from problems with splicing. However, our understanding of the mechanisms of splicing is rather incomplete. This proposal aims to improve our understanding of the splicing process through a range of biophysical and molecular biological approaches. This information should prove useful in understanding human development and disease.Read moreRead less
Evolution, structure and function of key components in a molecular machine. The project will provide the basis for training of students and personnel in the previously recognized priority "Genomes-Phenomes", still the central theme of modern biology. In particular,
collaborations established with the Los Alamos National Laboratory in New Mexico will transfer to Australia expertise in the cutting edge discipline of small angle scattering for analysis of biologically important molecules. Such tr ....Evolution, structure and function of key components in a molecular machine. The project will provide the basis for training of students and personnel in the previously recognized priority "Genomes-Phenomes", still the central theme of modern biology. In particular,
collaborations established with the Los Alamos National Laboratory in New Mexico will transfer to Australia expertise in the cutting edge discipline of small angle scattering for analysis of biologically important molecules. Such training is essential for developing a future pool of skilled Australian scientists to staff and utilise the major national infrastructure developments represented by the Replacement Research Reactor and Australian Synchrotron, as outlined in the National Research Priority "Frontier Technologies".Read moreRead less
Investigating the subunit interactions of a molecular protein import machine. The project will provide fundamental knowledge of how sophisticated natural molecular machines interact with their substrates in plants and animals. It will also provide the basis for training of students and personnel in a range of structural biology technologies including several that are not commonly used by biologists, but make use of two major facilities that have been invested in by our government, namely the Aus ....Investigating the subunit interactions of a molecular protein import machine. The project will provide fundamental knowledge of how sophisticated natural molecular machines interact with their substrates in plants and animals. It will also provide the basis for training of students and personnel in a range of structural biology technologies including several that are not commonly used by biologists, but make use of two major facilities that have been invested in by our government, namely the Australian Synchrotron and the OPAL Research Reactor.Read moreRead less
Structure and temperature adaptation of chaperonin TF55 from Sulfolobus solfataricus. Our work has future potential both for biotechnology and for medical therapies. The cages formed by chaperonin subunits and their ability to bind to specific targets could lead to their application as nano-vesicles, could facilitate expression of eukaryotic proteins in bacteria and could help to prevent or dissolve protein aggregates. With Australia's ageing population, we can expect an increasing prevalence of ....Structure and temperature adaptation of chaperonin TF55 from Sulfolobus solfataricus. Our work has future potential both for biotechnology and for medical therapies. The cages formed by chaperonin subunits and their ability to bind to specific targets could lead to their application as nano-vesicles, could facilitate expression of eukaryotic proteins in bacteria and could help to prevent or dissolve protein aggregates. With Australia's ageing population, we can expect an increasing prevalence of pathologies such as Alzheimer's and Parkinson's disease and other diseases that arise from protein mis-folding and aggregation, including myopathies and cataracts. A participation of chaperonins has been implicated in these age-related diseases and demands detailed structural and functional investigations.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
Cytoprotection By Erythropoietin In Hypoxia-ischaemia Of The Kidney And Brain
Funder
National Health and Medical Research Council
Funding Amount
$477,661.00
Summary
We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one ....We aim to make a significant research impact by describing the complex mechanisms responsible for protecting kidney and brain cells from stress caused by a lack of oxygen. In particular we will establish whether the compound erythropoietin (Epo), which occurs naturally in the human body but its human recombinant form can also be used as a treatment, may be useful in protecting cells from death following a shortage of oxygen. . We have already described how Epo can protect the kidney, but no one has yet described its action on kidney cell differentiation or its effect on structural and vascular support in the injured kidney. When might Epo treatment be effective? Could it protect against chronic renal disease? Likewise, whilst more very pre-term babies survive, this is a crucial period when they are at heightened sensitivity to lack of oxygen and they are at risk of brain damage and poor development because of lack of maturation of key structural cells in the brain. The role of Epo in aiding brain cell maturation and on blood vessel formation and function in this faulty development period is not known. Both of these health problems are major issues causing huge costs to society both financial and emotional. Despite the early evidence of a useful role for Epo in human disease treatment, current experimental and clinical data demonstrate the importance of further thorough investigation of mechanisms and cellular pathways that will underpin improvements in clinical outcomes. A particular strength of our project is that by comparing similarities and differences in the kidney and brain, we will be able to elucidate the mechanisms of action of Epo and its analogues.Read moreRead less
IDENTIFYING CONTROL ELEMENTS IN CHLOROPLAST GENE EXPRESSION. Energy from sunlight is captured by photosynthesis in plants, providing the basis for the terrestrial food chain. This process takes place in chloroplasts, subcellular structures that derived from photosynthetic bacteria a billion years ago. Chloroplasts have their own DNA, containing genes encoding the most important photosynthetic proteins. This project aims to provide the world’s best resources for the study of chloroplast genes. In ....IDENTIFYING CONTROL ELEMENTS IN CHLOROPLAST GENE EXPRESSION. Energy from sunlight is captured by photosynthesis in plants, providing the basis for the terrestrial food chain. This process takes place in chloroplasts, subcellular structures that derived from photosynthetic bacteria a billion years ago. Chloroplasts have their own DNA, containing genes encoding the most important photosynthetic proteins. This project aims to provide the world’s best resources for the study of chloroplast genes. In the process, we will discover how these important genes are regulated to provide photosynthetic proteins in the right amounts, in the right cells, at the right time. The knowledge and resources gained will facilitate improvement of photosynthetic function in future agricultural crops.Read moreRead less