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
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
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
Disaster risk reduction practices that leave nobody behind. This project aims to answer critical questions about how to assist people with disabilities (PWD) in disasters, what their support needs are and how they might help themselves to better prepare for disasters. Significance includes coupling a person-centred emergency preparedness tool with cross-sectoral processes to collect and use data about the support needs of PWD in emergencies, increase cross-sector communication and collaboration ....Disaster risk reduction practices that leave nobody behind. This project aims to answer critical questions about how to assist people with disabilities (PWD) in disasters, what their support needs are and how they might help themselves to better prepare for disasters. Significance includes coupling a person-centred emergency preparedness tool with cross-sectoral processes to collect and use data about the support needs of PWD in emergencies, increase cross-sector communication and collaboration between emergency managers and community services, and improve equitable access for PWD to community-level disaster risk reduction (DRR). The expected outcome will be the co-design of effective mechanisms that state & federal decision makers can use to scale-up disability-inclusive DRR across Australia.Read moreRead less
Confronting everyday harms: preventing abuse of people with disability. The findings of the Disability Royal Commission necessitate new approaches to prevent violence, abuse, neglect and exploitation. Framed by recognition theory, this project proposes empirical research with young people with cognitive disability, using a new concept of ‘everyday harms’ in their paid relationships. The results will inform early responses to poor quality interactions in disability support. The strategic alliance ....Confronting everyday harms: preventing abuse of people with disability. The findings of the Disability Royal Commission necessitate new approaches to prevent violence, abuse, neglect and exploitation. Framed by recognition theory, this project proposes empirical research with young people with cognitive disability, using a new concept of ‘everyday harms’ in their paid relationships. The results will inform early responses to poor quality interactions in disability support. The strategic alliances with the government, industry and community partners will develop a practice framework to prevent everyday harms and the escalation to abuse, and to promote safety and wellbeing. The research has policy benefits for capacity-building in the sector to act on the rights and voices of people with disability. Read moreRead less
Young people with cognitive disability: relationships and paid support. This project aims to improve the rights and wellbeing of young people with cognitive disability by exploring their relationship and interaction with paid support workers. The introduction of national individualised funding and support is a watershed in Australian disability policy. Understanding the role that paid support plays in the ongoing identity development of these young people is urgently needed to realise national p ....Young people with cognitive disability: relationships and paid support. This project aims to improve the rights and wellbeing of young people with cognitive disability by exploring their relationship and interaction with paid support workers. The introduction of national individualised funding and support is a watershed in Australian disability policy. Understanding the role that paid support plays in the ongoing identity development of these young people is urgently needed to realise national policy aspirations for people with disability of rights, choice, inclusion and independence. Using social geography and recognition theory, the project expects to deliver new understanding and improved practice around how paid support relationships can foster mutual care, respect and value at a critically important time in young people’s lives.Read moreRead less
Economic impacts of disease on older workers: Costs to government and individuals and opportunities for intervention. With an ageing workforce, Australia is at risk of having an inadequate workforce to ensure economic growth and to maintain sufficient taxation revenue to support future needs.
This project will provide fill substantial gaps in the Australian evidence the health conditions that keep older workers out of the labour market and that diminish their own immediate and long-term livi ....Economic impacts of disease on older workers: Costs to government and individuals and opportunities for intervention. With an ageing workforce, Australia is at risk of having an inadequate workforce to ensure economic growth and to maintain sufficient taxation revenue to support future needs.
This project will provide fill substantial gaps in the Australian evidence the health conditions that keep older workers out of the labour market and that diminish their own immediate and long-term livings standards and reduce funds available to government. We will address one of the most significant issues resulting fundamental changes to the demography of the Australian labour market and one is regularly raised by the Prime Minister and Treasurer in their speeches following the Intergenerational Report.Read moreRead less
The transition from secondary school to adulthood: Experiences and life outcomes for youth with an intellectual disability and their families. This project seeks to explore the challenges faced and outcomes achieved by students with an intellectual disability as they move from secondary school into adult life. The study will investigate the factors at an individual, educational, family, and societal level which positively and adversely affect outcomes for young people with an intellectual disab ....The transition from secondary school to adulthood: Experiences and life outcomes for youth with an intellectual disability and their families. This project seeks to explore the challenges faced and outcomes achieved by students with an intellectual disability as they move from secondary school into adult life. The study will investigate the factors at an individual, educational, family, and societal level which positively and adversely affect outcomes for young people with an intellectual disability and their families. Family impacts can include significant loss of income as parents may have to cease employment to care for their young adult who has limited employment or day placement options. Gaining the knowledge to minimise the disruption to family life, which often occurs at this time of transition, will lead to strengthening Australia's social and economic fabric.Read moreRead less
Improving employment outcomes for Australians with disability. This project aims to provide evidence about how to improve employment outcomes for people with disability. Nearly one in five adult Australians have a disability and just over half of these are in the labour force; a modest increase in employment rates will have significant social and economic benefits for people with disability and society. By collecting longitudinal quantitative (survey) and qualitative (interview) data at three ti ....Improving employment outcomes for Australians with disability. This project aims to provide evidence about how to improve employment outcomes for people with disability. Nearly one in five adult Australians have a disability and just over half of these are in the labour force; a modest increase in employment rates will have significant social and economic benefits for people with disability and society. By collecting longitudinal quantitative (survey) and qualitative (interview) data at three time points from over 1500 jobseekers with disability, critical information should be gained about how the characteristics of employment services, workplaces and jobseekers contribute to sustainable, meaningful employment for people with disability.Read moreRead less