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
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
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
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
Unravelling transthyretin amyloid, bounding ahead using wallabies. Each protein in our body has a unique shape that enables it to function correctly. For unknown reasons, some proteins can change their shape, aggregate with other proteins and stick to the outside of cells of major organs or nerves. This prevents those cells from working properly and results in disease. Transthyretin is a protein that changes shape and aggregates in the heart of most people over the age of 70. The disease is call ....Unravelling transthyretin amyloid, bounding ahead using wallabies. Each protein in our body has a unique shape that enables it to function correctly. For unknown reasons, some proteins can change their shape, aggregate with other proteins and stick to the outside of cells of major organs or nerves. This prevents those cells from working properly and results in disease. Transthyretin is a protein that changes shape and aggregates in the heart of most people over the age of 70. The disease is called Senile Systemic Amyloidosis (SSA). It is not known how or why this happens. There is no cure or therapy. This project will use transthyretins from human and wallaby to explore a possible cause of SSA. If our hypothesis is correct, we will propose preventative actions to reduce the incidence of SSA in the future.Read moreRead less
Molecular toxinology of Australia's lesser known venomous snakes. This proposal represents a tremendous opportunity for biodiscovery from venomous snakes. This will be achieved through the researchers' unique approach of investigating previously unmapped venom systems for divergent, bioactive proteins. An understanding of venomous animal protein evolution great potential in drug discovery and other commercial applications. This project will provide Australian graduate and post-graduate stude ....Molecular toxinology of Australia's lesser known venomous snakes. This proposal represents a tremendous opportunity for biodiscovery from venomous snakes. This will be achieved through the researchers' unique approach of investigating previously unmapped venom systems for divergent, bioactive proteins. An understanding of venomous animal protein evolution great potential in drug discovery and other commercial applications. This project will provide Australian graduate and post-graduate students with finely tuned skills in cutting edge methodological techniques and a fluent understanding of molecular evolution, preparing them to be internationally competitive scientists.Read moreRead less