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
Motor Functioning In Autism And Asperger's Disorder: Furthering Current Neurobehavioural And Clinical Definitions
Funder
National Health and Medical Research Council
Funding Amount
$354,932.00
Summary
While it is well known that autism and Asperger's disorder are associated with social, communicative, and behavioural symptoms, it is less well known that affected individuals also have considerable movement and coordination difficulties. For example, these children often have problems with hand writing, walking, hopping, skipping, catching, and running. These skills are very important for success at school; for example, if children are unable to participate in school sports they often feel isol ....While it is well known that autism and Asperger's disorder are associated with social, communicative, and behavioural symptoms, it is less well known that affected individuals also have considerable movement and coordination difficulties. For example, these children often have problems with hand writing, walking, hopping, skipping, catching, and running. These skills are very important for success at school; for example, if children are unable to participate in school sports they often feel isolated and rejected from the peer group. Also, hand writing problems have a significant impact on children's academic performance. Our previous research has suggested that there may be particular patterns of motor problems that characterise individuals with autism and Asperger's disorder. Our proposed research aims to use the kinds of 3D motion analysis technology used in the movie industry to capture exactly how people affected by these conditions move and respond to the environment. This study will enable us to highlight particular parts of the brain-motor circuitry that are affected by these disorders and will also enable us to more clearly distinguish how autism is different from Asperger's disorder. Ultimately, it is hoped that our motor investigations will lead to improved assessment and interventions for these disorders.Read moreRead less
3D Printed Food for People with Swallowing Disability. This project aims to identify ways that 3D food printing (additive manufacturing using real food in a device like a ink-jet printer) could be used to improve the visual appeal of puree meals for people with swallowing difficulty, who make up ~8% of the world's population. This study will be the first to include people with swallowing disability (e.g., related to cerebral palsy, stroke, older age) and their supporters in examining the views a ....3D Printed Food for People with Swallowing Disability. This project aims to identify ways that 3D food printing (additive manufacturing using real food in a device like a ink-jet printer) could be used to improve the visual appeal of puree meals for people with swallowing difficulty, who make up ~8% of the world's population. This study will be the first to include people with swallowing disability (e.g., related to cerebral palsy, stroke, older age) and their supporters in examining the views and experiences of stakeholders on the impact of 3D food printing on quality of life, enjoyment, participation, and safety. Outcomes include new knowledge on factors affecting the implementation of 3D food printing in disability and aged care services, to inform policy, practice, and future research.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
Assessing performance: designing a better performance management framework for disability employment services. The Australian Government is committed to providing the "best possible" service to assist people with disability find employment in the open labour market. This project will develop a performance management framework for disability employment services which includes indicators of service quality as well as employment outcomes.
Discovery Early Career Researcher Award - Grant ID: DE120102221
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
Investigating the susceptibility of native vegetation edges to alien plant invasion: a quantitative study to help prevent and control invasive species. Alien plant invasion is a major threat to biodiversity in national parks and nature reserves. Determining the relative influence of plant characteristics, number of alien plant seeds and availability of light, water and nutrients on weed invasion will indicate what prevention and control strategies should be used to combat invasive plants.
Deafblind communication: Building professional competencies . This project aims to improve the quality of interpreting/support services provided to deafblind Australians by analysing the communication strategies used by deafblind sign language users. Many deafblind people use a modified form of Auslan (Australian Sign Language) to communicate, yet little is known about how interpreters or support workers should adapt their signing when working with deafblind clients to ensure effective communica ....Deafblind communication: Building professional competencies . This project aims to improve the quality of interpreting/support services provided to deafblind Australians by analysing the communication strategies used by deafblind sign language users. Many deafblind people use a modified form of Auslan (Australian Sign Language) to communicate, yet little is known about how interpreters or support workers should adapt their signing when working with deafblind clients to ensure effective communication. This project would develop evidence-based training and resources for these professionals. This should provide significant benefits such as improved communication between deafblind clients and professionals, and enhancing the efficiency and effectiveness of support service provision for deafblind people.Read moreRead less
Predicting the causes and consequences of plant invasions. Invasive plants are one of the most costly and significant environmental threats in Australia. To deal with this threat we need to understand how and why certain plant species are able to invade into and dominate native communities. The aim of this project is to uncover the rules that govern this environmental threat. The project endeavours to use theory to predict the outcomes that would be observed given different underlying rules, and ....Predicting the causes and consequences of plant invasions. Invasive plants are one of the most costly and significant environmental threats in Australia. To deal with this threat we need to understand how and why certain plant species are able to invade into and dominate native communities. The aim of this project is to uncover the rules that govern this environmental threat. The project endeavours to use theory to predict the outcomes that would be observed given different underlying rules, and then test these predictions with field experiments. By uncovering the rules that govern invasions, this project could provide fundamental knowledge to assist in managing the environmental threat posed by new and emerging weeds.Read moreRead less
Building insights of our largest terrestrial carbon sink: rangelands soils. Rangelands soils represent Australia’s largest carbon sink. Yet, little is known about their potential for carbon sequestration or their vulnerability to climate and environmental change. This project leverages investments in national terrestrial observation platforms and integrates previous research outputs to develop new methods to measure and build understanding of soil carbon composition and dynamics in rangeland eco ....Building insights of our largest terrestrial carbon sink: rangelands soils. Rangelands soils represent Australia’s largest carbon sink. Yet, little is known about their potential for carbon sequestration or their vulnerability to climate and environmental change. This project leverages investments in national terrestrial observation platforms and integrates previous research outputs to develop new methods to measure and build understanding of soil carbon composition and dynamics in rangeland ecosystems. Under a framework that connects detailed measurements and small-scale processes, with machine-learning, data-model assimilation and large-scale next-generation biogeochemical modelling, it’ll allow more accurate predictions of soil carbon change and better decision-making to guide sustainable rangelands management.Read moreRead less
A Longitudinal Study Of Psychopathology In People With Intellectual Disability
Funder
National Health and Medical Research Council
Funding Amount
$999,803.00
Summary
This project will further develop the research opportunities of an internationally unique 15 year follow up study of the mental health of young Australians with ID. We have shown that this group has 2-3 times the risk of suffering serious emotional and behavioural problems that are an added heavy burden on the individual, their family and carers and the community. These problems often are not recognised but are as common as schizophrenia in the community. The study will continue to use a combina ....This project will further develop the research opportunities of an internationally unique 15 year follow up study of the mental health of young Australians with ID. We have shown that this group has 2-3 times the risk of suffering serious emotional and behavioural problems that are an added heavy burden on the individual, their family and carers and the community. These problems often are not recognised but are as common as schizophrenia in the community. The study will continue to use a combination of questionnaire survey and in depth interviews of the young adults and their families or carers to track the course of their mental health. The study commenced in 1990 with nearly 1000 young people with ID aged 4-18 years and their progress has been reviewed every 2-3 years in over 75% of the original group. During the next 5 years we plan to follow their mental health during the critical stage of young adult life. During this time there is the greatest risk of mental illnesses such as depression and schizophrenia and the stresses of adjusting to new daily occupations, independent living or residential care and social contact away from the family. We will be able to study the specific emotional and behavioural problems faced by young adults with the main known causes of ID such as Down, Fragile X, Prader Willi and William Syndromes, as well as those who have autism. The great benefit of a long term follow up study is that it allows us to study the links between earlier family environmental, psychological and biological factors and subsequent mental health problems. We can also demonstrate the impact that mental illness in a young person with ID has on the family and parental mental health. The findings have implications for better diagnosis, improved care and management, early intervention and prevention of these common severe and under recognized mental health problems in this disadvantaged group of young Australians and their families and carers.Read moreRead less