Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$285,990.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin i ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. Recent studies using Baker's yeast have shown that the deletion of frataxin results in the accumulation of toxic iron in the mitochondrion. More recently, a variety of studies have shown that FA patients have iron loading within their cells. The iron build-up may cause severe damage. At present, the role of frataxin in mammalian mitochondrial iron metabolism is unknown. Our preliminary studies demonstrate that frataxin is down-regulated by either erythroid differentiation or the haem precursor protoporphyrin IX (Becker and Richardson, submitted). These data strongly suggest a role for frataxin in iron metabolism. In the present study we will continue to assess if frataxin plays a role in the way cells handle iron. Using a unique model of mitochondrial iron overload developed in my lab (Richardson et al. (1996) BLOOD 87:3477), we will extensively investigate the iron metabolism of the mitochondrion in order to determine the function of frataxin and its role in Friedreich's ataxia. In addition, we have developed a series of new drugs known as iron chelators that can enter the mitochondrion due to their high lipid solubility (Becker and Richardson 1999 J. Lab. Clin. Med. 134:510). These latter drugs are far more effective than the chelator currently used to treat iron overload, desferrioxamine (DFO). Indeed, our chelators have been designed to result in high iron chelation efficacy but low toxicity (see Becker and Richardson, 1999). This exciting research may be crucial in understanding the development of FA and in creating new therapies such as the use of iron chelators.Read moreRead less
Mitochondrial Iron Overload And Friedreich's Ataxia: The Role Of Frataxin In Iron And Haem Metabolism
Funder
National Health and Medical Research Council
Funding Amount
$606,000.00
Summary
Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that c ....Friedreich's ataxia (FA) is due to the lack of a protein known as frataxin. A variety of studies using Baker's yeast and conditional frataxin knockout (KO) mice have shown that deletion of frataxin leads to the accumulation of toxic iron in their mitochondrion. More recently, a variety of studies have shown that FA patients have iron-loading within their mitochondrion. Iron in the highly redox active environment of the mitochondrion could contribute to the generation of cytotoxic radicals that cause severe damage. Further, cells deficient in frataxin are sensitive to oxidant stress and Fe chelators rescue oxidant-mediated death of cells from FA patients. Indeed, free radical scavengers have shown to be of use in the treatment of this disease. Studies in DR's lab during this NHMRC grant have shown that frataxin is down-regulated by erythroid differentiation or the haem precursor, protoporphyrin IX (BLOOD 2002;99:3813-22). These data indicate a role for frataxin in Fe metabolism and the pathogenesis of FA. In this study we will continue to examine the role of frataxin in the way cells handle Fe using experimental models developed under the current NHMRC grant. These include transfected cell lines with low frataxin expression generated using an expression vector containing anti-sense frataxin cDNA. Further we obtained the frataxin conditional KO mouse and generated a breeding colony. These animals display many of the pathological features of FA and are the best current model of the disease. Indeed, they will be critical for assessing the role of frataxin in Fe metabolism and as a model to test the ability of Fe-binding drugs to prevent the pathology observed. We designed lipid-soluble chelators that can enter the mitochondrion to bind Fe (Biochim Biophys Acta 2001;1536:133-140) and these ligands will be tested to prevent disease progression in the KO mice. This exciting research is crucial for understanding the pathogenesis of FA and in creating new therapies.Read moreRead less
Mechanisms Of Oxidised Protein Accumulation In Ageing Cells
Funder
National Health and Medical Research Council
Funding Amount
$429,000.00
Summary
Australia has one of the world's most rapidly ageing populations. It is estimated that in 30 years time over 30% of the population will be over 65; many will suffer from a debilitating, age-related disease. The diseases of ageing represent one of the major health challenges this century. Despite their increasing incidence, our understanding of the underlying causes is limited. A common feature is the accumulation of damaged proteins in cells and tissues. Damaged proteins are usually broken down ....Australia has one of the world's most rapidly ageing populations. It is estimated that in 30 years time over 30% of the population will be over 65; many will suffer from a debilitating, age-related disease. The diseases of ageing represent one of the major health challenges this century. Despite their increasing incidence, our understanding of the underlying causes is limited. A common feature is the accumulation of damaged proteins in cells and tissues. Damaged proteins are usually broken down by the cells and replaced, but in many age-related diseases this process fails. The most common source of protein damage is attack by oxygen-derived free radicals. These are by-products of our body's need for oxygen and can originate from atmospheric pollutants. Oxygen rusts metal, makes fat go rancid and can cause irreparable damage to proteins and other biological molecules. Free radical damage contributes to the development of many age-related diseases such as atherosclerosis and neurodegenerative diseases such as Alzheimer's disease. The accumulation of damaged proteins can cause cell death. Our knowledge of the mechanisms by which cells remove proteins damaged by oxygen and the reasons for their accumulation is limited. In this project we will use a novel technique we have developed to generate oxidised proteins in ageing cells. We will identify cellular mechanisms required for the efficient removal of damaged proteins and those mechanisms which fail in ageing cells. We will focus on a group of proteins which protect damaged proteins from aggregating and accumulating and we will examine how we can prevent the accumulation of oxidised proteins by stimulating the body s defence mechanisms. Since the population of Australia is ageing, diseases of ageing are going to consume an increasing amount of the national health budget. A better knowledge of these cellular mechanisms will allow us to design effective prevention and treatment strategies which are at present lacking.Read moreRead less
NEU-HORIZONS: The Neuroprotection And Therapeutic Use Of Riluzole For The Prevention Of Oxaliplatin Neurotoxicity Study.
Funder
National Health and Medical Research Council
Funding Amount
$382,402.00
Summary
Colorectal cancer is the second most commonly diagnosed cancer in Australia, with more than 13500 cases recorded annually. Oxaliplatin is an effective chemotherapy for the treatment of colorectal cancer. The major side-effect of oxaliplatin is the development of nerve damage that leads to loss of feeling in the hands and feet and significant disability. The aim of this study is to conduct a trial of a new treatment for oxaliplatin-induced nerve damage.
Surveillance Of LGV Chlamydia Trachomatis Types Among Men Who Have Sex With Men (MSM)
Funder
National Health and Medical Research Council
Funding Amount
$194,875.00
Summary
Chlamydia is a common sexually transmitted infection (STI) caused by the bacterium, Chlamydia trachomatis (CT). Annually, 50 million new cases of chlamydia are estimated to occur worldwide which if untreated, can lead to serious complications such as pelvic inflammatory disease and infertility in women and epididymitis in men. Over the past decade, there has been a sharp increase in diagnoses of chlamydia in Australia, coinciding with a reported upsurge in sexual risk behaviour (increased partne ....Chlamydia is a common sexually transmitted infection (STI) caused by the bacterium, Chlamydia trachomatis (CT). Annually, 50 million new cases of chlamydia are estimated to occur worldwide which if untreated, can lead to serious complications such as pelvic inflammatory disease and infertility in women and epididymitis in men. Over the past decade, there has been a sharp increase in diagnoses of chlamydia in Australia, coinciding with a reported upsurge in sexual risk behaviour (increased partner numbers and-or practices of unprotected sex), particularly among men who have sex with men (MSM). In addition, there are current outbreaks of an invasive CT strain, causing lymphogranuloma venereum (LGV), throughout Western Europe, with cases now reported in the USA. LGV can lead to severe anogenital ulcers, which can increase transmission of HIV, hepatitis C, and other STIs. With growing international travel, the likelihood of LGV outbreaks in Australia, particularly in MSM, is increased. Recently, isolated cases of LGV have been noted in MSM attending Sydney and Melbourne Sexual Health Centres, indicating LGV is possibly already in circulation. Since we know little about circulating CT types in Australia it would be difficult to assess the burden of an LGV outbreak. Due to increasing CT infections and likely risk of increased HIV transmission, particularly with LGV strains, surveillance of CT genotypes in Australia, especially in MSM, is important. The purpose of this study is to type CT strains in our population by looking at their genetic makeup. CT-positive specimens from Melbourne and Sydney will be used to identify CT types in circulation and to assess if LGV types are present. The knowledge obtained from this study will be novel and invaluable, and could contribute considerably to the development of improved disease prevention and intervention strategies, including the design of vaccines.Read moreRead less
Mechanisms Of Proteolysis Of Proteins Containing Oxidised Amino Acids
Funder
National Health and Medical Research Council
Funding Amount
$406,320.00
Summary
There is evidence that during ageing, and age-related diseases, proteins which have been chemically modified by oxidation accumulate in the body, and may have deleterious effects. Oxidation of proteins is a process akin to that by which fats go rancid. It has been demonstrated by the applicants to be an important process in formation of cataracts, and in development of the blood vessel disease, atherosclerosis, which is responsible for most heart attacks and stroke. Other important age-related d ....There is evidence that during ageing, and age-related diseases, proteins which have been chemically modified by oxidation accumulate in the body, and may have deleterious effects. Oxidation of proteins is a process akin to that by which fats go rancid. It has been demonstrated by the applicants to be an important process in formation of cataracts, and in development of the blood vessel disease, atherosclerosis, which is responsible for most heart attacks and stroke. Other important age-related diseases, such as Alzheimer s disease and other neurological disorders, are also claimed to be associated with deranged protein oxidation, and accumulation of oxidised products. There is clear evidence that certain defensive mechanisms, such as those acting to remove invading organisms and clear wounds, are also associated with an enhanced production of oxidised proteins. Perhaps the most important component of defense against oxidised proteins is their removal by complete breakdown to constituent components, and excretion. Normally, the machinery for breakdown of proteins is in vast excess over the required rate of degradation. However, clearly in these conditions of accumulation of oxidised proteins, this is no longer the case, or no longer suffices. Mechanisms by which oxidised proteins are degraded are poorly understood, and quite controversial. Therefore, the present studies bring to bear a new approach to studying this issue, which has been developed by the applicants. The aim is to reveal mechanisms involved in the breakdown of proteins containing oxidised amino acids, both in cellular systems, and in vivo. Such an understanding may allow us to envisage how to remove oxidised proteins by therapeutic means and therefore interfere with the development of age-related diseases such as Alzheimer s disease and cataract formation and the diseases of the blood vessels associated with attack and stroke.Read moreRead less
A Case-control Study Of Rotavirus Vaccine Effectiveness Against Gastroenteritis Hospitalisation Of Children In The NT
Funder
National Health and Medical Research Council
Funding Amount
$465,859.00
Summary
Almost 1 out of 5 children in remote Aboriginal communities are hospitalised with diarrhoea caused by rotavirus. This study will evaluate the impact of rotavirus vaccination in preventing these hospitalisations. In addition to making sure that vaccination works and that those at highest risk are receiving the benefits, it will assess the indirect impact against other causes of diarrhoea providing, critical information relevant to the vaccine's broader introduction in developing country settings.
EPITHELIAL ION TRANSPORT DEFECTS IN CYSTIC FIBROSIS: PATHOPHYSIOLOGY AND TREATMENT
Funder
National Health and Medical Research Council
Funding Amount
$290,440.00
Summary
The thin layer of fluid covering the surface of the air passages acts to protect the airway surface from drying. This fluid also allows the hair-like projections, or cilia, on the top of the airway cells to beat more effectively. The volume and composition of this fluid is determined by the movement of salt and water across the mucous membranes of the air passages. The importance of this fluid is shown by the problems that occur in Cystic Fibrosis (CF), the most common lethal inherited disease a ....The thin layer of fluid covering the surface of the air passages acts to protect the airway surface from drying. This fluid also allows the hair-like projections, or cilia, on the top of the airway cells to beat more effectively. The volume and composition of this fluid is determined by the movement of salt and water across the mucous membranes of the air passages. The importance of this fluid is shown by the problems that occur in Cystic Fibrosis (CF), the most common lethal inherited disease affecting Australians. In CF, altered salt transport causes drying of the airway surface which impairs the working of the cilia. This leads to retention of mucous in the airway with repeated bacterial infections damaging the lungs. Simple tests have been designed to directly measure the movement of salt across the surface of the nasal passage using a fine soft rubber tube. Movement of mucous in the nose is measured using other simple techniques that are currently used diagnostically. Together, these tests in the nose provide vital information about how the surface of normal human airway moves salt, water and mucous. Any differences found in CF patients will then give us a good idea of the problems found in the CF lung. We will study the interactions between calcium, sodium and chloride in the fluid lining the airways, measuring changes in salt and mucous movement. A range of testing procedures will be used in human volunteers, anaesthetised mice and isolated tissues from sheep. We have already demonstrated important links between the fluid lining the airways and salt movement, and we expect that this may lead to the development of new treatments for Cystic Fibrosis. This therapy will focus on treating the lung problems of CF patients, the major cause of disability. We anticipate that this preventative therapy may offer real benefits in the fight to cure CF.Read moreRead less
Mechanism Of Action Of Sec1p-like Proteins In Membrane Trafficking
Funder
National Health and Medical Research Council
Funding Amount
$234,936.00
Summary
One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has ....One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has developed a complex assembly line of modifications that are added to proteins in a specific order as they travel to their final destination within the cell. This necessitates the accurate passage of molecules between compartments, a process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between all of the various intracellular compartments it is necessary to employ complex machinery to guide and check that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that we can apply our knowledge to understanding many different disease states.Read moreRead less
Mechanism Of Action Of Sec1p-like Proteins In Membrane Trafficking.
Funder
National Health and Medical Research Council
Funding Amount
$440,250.00
Summary
One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has ....One of the most important evolutionary changes that has occurred is the development of intracellular compartments. All eukaryotic cells possess numerous membrane-encased structures which provide the basis for intracellular specialisation. For example, in order to degrade unwanted components cells have developed degradative enzymes. It is vital for the cell that these enzymes are sequestered away from other cellular components to avoid destruction of valuable molecules. In addition, the cell has developed a complex assembly line of modifications that are added to proteins in a specific order as they travel to their final destination within the cell. This necessitates the accurate passage of molecules between compartments, a process known as vesicle transport. To orchestrate the complex network of vesicular transport steps between all of the various intracellular compartments it is necessary to employ complex machinery to guide and check that these steps occur with high fidelity. The goal of our research proposal is to define the function of one of the molecules involved in this control process, the so-called Sec1p proteins. The strength of our proposal lies in the diversity of our approach. We intend to explore the molecular advantages of a relatively simple eukaryotic organism, a yeast cell, and apply the findings obtained from this cell to a more complex but highly related vesicular transport process; that of the insulin-regulated movement of a glucose transporter in mammalian fat and muscle cells. While we intend to apply our findings to the treatment of patients with diabetes, it is our ultimate goal to be able to learn more about this fundamental cell biological process so that we can apply our knowledge to understanding many different disease states.Read moreRead less