Cellular Effects Of Glucocerebrosidase (GBA) Mutations In Lewy Body Diseases
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
Approximately 1 in 100 people are carriers of mutations in the glucocerebrosidase (GBA) gene and are at considerably greater risk of diseases characterised clinically by parkinsonism and by the presence of Lewy body-related pathology. This study will provide tissue-based evidence of the cellular lipid and protein changes relating to Lewy body formation in patients with GBA mutations, providing the information necessary to identify the pathways and mechanisms involved.
Alpha-synuclein Metabolism In Human Neurodegenerative Disease
Funder
National Health and Medical Research Council
Funding Amount
$381,430.00
Summary
Alpha-synuclein is an abundant brain protein of unknown function. Gene mutations have been linked to rare cases with inherited Parkinson s disease. Now this protein is believed to play an important role in all forms of Parkinson s disease, Lewy body dementia, and multiple system atrophy. These diseases are designated as synucleinopathies to emphasize the potential importance of alpha-synuclein in these disease. Recent studies suggest alpha-synuclein may also contribute to many other human diseas ....Alpha-synuclein is an abundant brain protein of unknown function. Gene mutations have been linked to rare cases with inherited Parkinson s disease. Now this protein is believed to play an important role in all forms of Parkinson s disease, Lewy body dementia, and multiple system atrophy. These diseases are designated as synucleinopathies to emphasize the potential importance of alpha-synuclein in these disease. Recent studies suggest alpha-synuclein may also contribute to many other human diseases, including Alzheimer s disease. The reason how and why alpha-synuclein is involved in so many human neurological diseases is not clear. We recently discovered that alpha-synuclein in normal human brain exists in multiple form of N-terminal fragments, presumably generated through certain endogenous enzymes. These cleaved products are markedly increased in Parkinson s disease. Studies by other groups suggest alpha-synuclein and fragments may be released to the cerebrospinal fluids. Based on these findings, we hypothesize that alpha-synuclein is modified by specific enzymes in neurons and released. This is probably a normal alpha-synuclein metabolic pathway whose homeostasis may be, for reasons yet to be understood, altered in synucleinopathies. Similar mechanism may be also involved in other common diseases in which the protein is believed to play a role. This project aims to elucidate the potential role of alpha-synuclein metabolism in Parkinson s and related diseases by examining alpha-synuclein metabolites in the brains affected by these diseases. Results from this grant will provide new information about alpha-synuclein metabolism in neurons, new insights into the mechanistic involvement of alpha-synuclein in these neurodegenerative diseases. Antibody reagents generated from this study may be valuable in neuropathological and clinical assessment of changes in synucleinopathies.Read moreRead less
Alzheimer's Disease And Dementia With Lewy Bodies: How Different Are They?
Funder
National Health and Medical Research Council
Funding Amount
$565,500.00
Summary
Dementia is a devastating disorder, taking the individuals mind. As the population ages, a significant proportion become demented, impacting on these individuals, their families and the community as a whole (Federal and State budgets for this disorder are costed in the billions). There are many cellular causes of dementia, the most frequent being considered Alzheimer's disease. However, many people currently thought to have Alzheimer's disease have another dementia cause - dementia with Lewy bod ....Dementia is a devastating disorder, taking the individuals mind. As the population ages, a significant proportion become demented, impacting on these individuals, their families and the community as a whole (Federal and State budgets for this disorder are costed in the billions). There are many cellular causes of dementia, the most frequent being considered Alzheimer's disease. However, many people currently thought to have Alzheimer's disease have another dementia cause - dementia with Lewy bodies. This study aims to determine 1) how common these two types of dementias are (currently unknown) 2) how better to diagnose them and tell them apart 3) how badly the brain is affected by each disorder and 4) whether the same genes are involved in both disorders. The knowledge we will gain will allow better diagnosis of the cellular causes of dementia, knowledge necessary for rational treatment.Read moreRead less
A Randomised Controlled Trial To Prevent Primigravid Excessive Gestational Weight Gain And Postpartum Weight Retention
Funder
National Health and Medical Research Council
Funding Amount
$505,412.00
Summary
Excessive weight gain in pregnancy and weight retention 12 months post birth place women at a greater risk for the development of overweight and obesity. This study responds to the urgent need to design effective interventions to prevent excessive weight gain in pregnancy and postpartum weight retention. A health coaching intervention has been designed to address this urgent need, and its effectiveness will be evaluated in a randomised controlled trial with first time pregnant women.
Heart failure is a severely debilitating condition with a poor prognosis. It is characterized by retention of fluid and high nervous activity especially to the kidneys and the heart. Even with the best current treatment available, patients with heart failure still suffer from abnormally high nerve activity to the further detriment of this condition. The successful completion of this project will provide considerable insight into the role of the brain in the elevated nerve activity in heart failu ....Heart failure is a severely debilitating condition with a poor prognosis. It is characterized by retention of fluid and high nervous activity especially to the kidneys and the heart. Even with the best current treatment available, patients with heart failure still suffer from abnormally high nerve activity to the further detriment of this condition. The successful completion of this project will provide considerable insight into the role of the brain in the elevated nerve activity in heart failure. It will also provide us with a significant understanding of the role in reflex sympathetic nerve regulation of an important brain region known as the hypothalamic paraventricular nucleus (PVN). Our findings will help us understand the nature of the neurotransmitters contributing to the reflex nerve regulation and the specific neurons within the PVN involved. This knowledge could help us to identify novel potential therapeutic targets within the brain to alleviate the problems observed in heart failure.Read moreRead less
The Metabolic Effects Of Oestrogens And SERMs: Regulatory Interactions With The GH-IGF-system In Health And Disease
Funder
National Health and Medical Research Council
Funding Amount
$379,142.00
Summary
This project extends work aimed at understanding how GH and sex hormones work together to optimise physical health in women and men. It addresses the benefits and safety of oestrogen compounds in relation to their effects on body fat and muscle (body composition). Oestrogen compounds are among the most widely used medicines and include tradition oestrogens (female hormone) and synthetic oestrogens called SERMs. Oestrogens are used in young women as oral contraception and in the postmenopause for ....This project extends work aimed at understanding how GH and sex hormones work together to optimise physical health in women and men. It addresses the benefits and safety of oestrogen compounds in relation to their effects on body fat and muscle (body composition). Oestrogen compounds are among the most widely used medicines and include tradition oestrogens (female hormone) and synthetic oestrogens called SERMs. Oestrogens are used in young women as oral contraception and in the postmenopause for replacement therapy. Body composition is an important determinant of fitness and health. Obesity reduces fitness and increases the risk of diabetes and heart attacks while muscle loss causes weakness and frailty. GH is a major regulator of body composition; it acts by breaking down fat and building muscle mass. We discovered that oestrogens, when taken as a tablet interferes with the action of GH and causes detrimental changes in body composition. On the positive side, we have exploited the GH blocking action to treat acromegaly. This is a debilitating disease of excessive GH production from a pituitary tumour and for which available drug treatments are very expensive and require injection. The effects of SERMs on body composition are unknown. SERMs are interesting compounds because they act like oestrogens in some but as oestrogen blockers in other tissues. These are widely used in the treatment of breast cancer and osteoporosis. The extent to which they interfere with the action of GH has not been studied. They may exert additional effects because they act on the pituitary gland to reduce the secretion of GH. They may also prove to be effective in acromegaly which could extend their usefulness to men. In summary, the work will provide important information on the long-term benefits of SERMs in patient groups that tend to be frail. It may also prove to be a simple and inexpensive treatment for acromegaly.Read moreRead less
The Role Of Liver Fructose-1,6-phosphatase (FBPase) In Body Weight Regulation
Funder
National Health and Medical Research Council
Funding Amount
$494,718.00
Summary
We have shown that fructose-1,6-bisphosphatase (FBPase), an enzyme important in producing sugar from the liver and one that is connected to Type 2 diabetes, does not cause an increase in sugar production when there is more of the enzyme in mouse livers. It does, however, lower both body weight and the amount of food the mice consume. We therefore hypothesise that liver FBPase is important in controlling body weight in humans and our project aims to find out exactly how and why this happens.