Identifying Novel Genes Causing Cytochrome C Oxidase (COX) Deficiency
Funder
National Health and Medical Research Council
Funding Amount
$426,917.00
Summary
Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the uniqu ....Our bodies convert food into energy in tiny cellular power plants called mitochondria. Each year about 50 Australian children inherit disorders of mitochondrial energy generation. The most severe disorders cause infant death, while others cause degenerative diseases in later life, particularly affecting brain and muscle. In most cases we lack effective treatments. The genetic causes of mitochondrial disorders are incredibly diverse, with over 70 disease genes known. Some are located on the unique mitochondrial DNA we inherit only from our mothers. Many more genes await discovery. This study focuses on the mitochondrial disorder cytochrome c oxidase (COX) deficiency, for which we have diagnosed 80 Australian patients. COX requires 13 separate components to be assembled together in order to work properly, but mutations in the genes encoding these components are not present in most patients. We believe that the most common problems will be in genes involved in assembling the components rather than in the components themselves. We will use a number of methods to pinpoint where in the genome the disease genes are located. A key to our strategy is identifying patients likely to have mutations in the same gene. We have identified two such groups, and will do studies that involving fusing two cell lines together to confirm they have the same disorder. We will then perform genetic mapping to look for regions of similarity in the genome using DNA (SNP) chips. We will test how well the genes in such regions are expressed, whether we can correct the problem in cultured skin cells by introducing a healthy copy of that chromosome, and look for gene mutations. Identifying these genes will allow us to improve future diagnosis and prevention and may allow us to develop new methods of treatment. Milder mitochondrial problems also contribute to a range of more common diseases such as diabetes and Alzheimer disease, so any new treatments could potentially have wide applicationRead moreRead less
Rapid mapping of genes for complex traits. This project will develop a new resource that will allow rapid identification of genes controlling complex traits. This world-leading resource will improve knowledge of diseases like diabetes and neurological diseases.
Molecular Genetics Of The Host Response Defect In Cystic Fibrosis
Funder
National Health and Medical Research Council
Funding Amount
$564,690.00
Summary
Cystic fibrosis is the most common lethal genetic disease in Caucasian populations. Affected individuals suffer from a number of symptoms but the most serious is a chronic infect with the bacterial pathogen Pseudomonas aeruginosa. The sustained lung inflammation caused by infection with Pseudomonas aeruginosa ultimately destroys the structure of the lung to the point where it can no longer function. Gene therapy has been suggested as a possible treatment for the disease but another approach is t ....Cystic fibrosis is the most common lethal genetic disease in Caucasian populations. Affected individuals suffer from a number of symptoms but the most serious is a chronic infect with the bacterial pathogen Pseudomonas aeruginosa. The sustained lung inflammation caused by infection with Pseudomonas aeruginosa ultimately destroys the structure of the lung to the point where it can no longer function. Gene therapy has been suggested as a possible treatment for the disease but another approach is to identify the CF specific aspects of the inflammatory response and target those for therapeutic development. In our previous work we have identified several strong candidates for the inflammatory molecules in the CF lung and in this application we will test those candidates to see whether they play a major role in CF lung disease.Read moreRead less
Developing methods for the analysis of massively parallel sequencing data in family studies. This project will develop analytical methods to use the latest, high-throughput method of generating sequencing data, i.e. the letters of the human genome alphabet. These tools will be used to identify the causal mutations in families with inherited disorders, leading to diagnostic tests for these families.
The extent, causes and implications of pleiotropy among complex traits. The project seeks to understand how a DNA mutation can affect many characters or traits. Many traits are called complex because they are controlled by a very large number of genes, most of which have small effects. Complex traits include traits important in medicine (such as susceptibility to heart disease) and in agriculture (such as tenderness of meat). Because there are many genes affecting each trait, most genes have sma ....The extent, causes and implications of pleiotropy among complex traits. The project seeks to understand how a DNA mutation can affect many characters or traits. Many traits are called complex because they are controlled by a very large number of genes, most of which have small effects. Complex traits include traits important in medicine (such as susceptibility to heart disease) and in agriculture (such as tenderness of meat). Because there are many genes affecting each trait, most genes have small effects which makes them hard to identify. The fact that a mutation that has a small effect on a complex trait also has a larger effect on a less complex trait may help us to identify the mutation and use it in agriculture or medicine.Read moreRead less
The transcriptional co-repressor C-terminal Binding Protein (CtBP) in metabolic control. This project will provide insights into the genes that regulate the storage of fat. We will learn about basic biology but will also discover mechanisms that may be used to influence fat storage in human health. We will also consolidate Australia's expertise in the use of the genetic model organism, the worm C. elegans, and validate the findings in mammalian systems. Finally, the process of training young sci ....The transcriptional co-repressor C-terminal Binding Protein (CtBP) in metabolic control. This project will provide insights into the genes that regulate the storage of fat. We will learn about basic biology but will also discover mechanisms that may be used to influence fat storage in human health. We will also consolidate Australia's expertise in the use of the genetic model organism, the worm C. elegans, and validate the findings in mammalian systems. Finally, the process of training young scientists in these modern systems, will also equip future researchers to make additional contributions to Australia's research output.Read moreRead less
RNA splicing: factors and mechanisms. Most primary gene transcripts must have their noncoding intronic sequences spliced out before the mRNA can be translated. Moreover, alternative splicing enables cells to generate a far more proteins than there are genes in the nucleus. Based on our proven success with ZNF265 we will isolate novel RNA interactors and their partners, colocalize these in intranuclear compartments, and elucidate their effect on pre-mRNA splicing. This will provide timely spin-of ....RNA splicing: factors and mechanisms. Most primary gene transcripts must have their noncoding intronic sequences spliced out before the mRNA can be translated. Moreover, alternative splicing enables cells to generate a far more proteins than there are genes in the nucleus. Based on our proven success with ZNF265 we will isolate novel RNA interactors and their partners, colocalize these in intranuclear compartments, and elucidate their effect on pre-mRNA splicing. This will provide timely spin-offs to the Human genome Project and EST sequence information, where the finding of only approx. 30,000 genes in our genome highlights the important role of alternative splicing in generating the large proteome repertoire of cells. This will bring considerable benefits to science, society, and the biotech industry.Read moreRead less
Genetic dissection of a regulatory deubiquitlyation network. The potential impact of this work is widespread, because although it is known that ubiquitlyation has regulatory consequences in multicellular eukaryotes, individual networks have not been completely described in higher eukaryotes. Knowledge gained about fundamental processes in the A. nidulans model system is directly applicable to fungi used in biotechnology in the food, beverage, enzyme and pharmaceutical production industries, and ....Genetic dissection of a regulatory deubiquitlyation network. The potential impact of this work is widespread, because although it is known that ubiquitlyation has regulatory consequences in multicellular eukaryotes, individual networks have not been completely described in higher eukaryotes. Knowledge gained about fundamental processes in the A. nidulans model system is directly applicable to fungi used in biotechnology in the food, beverage, enzyme and pharmaceutical production industries, and to fungal pathogens. Since the fungal genes that form the basis of this project are conserved in higher eukaryotes including humans, the knowledge will be transferable to these systems. A further benefit that cannot be overstated is the research education and training opportunities provided.
Read moreRead less
A new mechanism of gene regulation. This project will advance our knowledge of how genes are switched on and off, by focusing on a very common class of gene regulatory proteins known as zinc finger proteins. The results of this study will improve our understanding of the fundamental molecular events that underpin gene regulation and how we might control it in fields such as biotechnology and gene therapy.
New mechanisms of DNA recognition by zinc-finger domains. The work described in this proposal carries long-term benefits to the health of Australians. Many debilitating diseases, including many varieties of cancer, arise as a result of a breakdown in the normal regulation of gene transcription. It is only once we have a thorough understanding of transcriptional regulation in normal organisms that we will be in a position to devise effective therapies to deal with the disorders that result from a ....New mechanisms of DNA recognition by zinc-finger domains. The work described in this proposal carries long-term benefits to the health of Australians. Many debilitating diseases, including many varieties of cancer, arise as a result of a breakdown in the normal regulation of gene transcription. It is only once we have a thorough understanding of transcriptional regulation in normal organisms that we will be in a position to devise effective therapies to deal with the disorders that result from aberrant gene expression. Our proposed research program also provides the opportunity to train younger scientists in state-of-the-art molecular and structural biology, thus representing a significant national benefit. Read moreRead less