The future of cancer therapy lies in the tailoring of treatment to the characteristic of individual tumour. We have previously identified a subset of breast tumours that are characterised by the presence of large excess of proteins called D-type cyclins. Similar overexpression of cyclin D1 has been shown to lead to the development of cancer in mammary gland in animal models. In normal cells, D-type cyclins are degraded rapidly, therefore the regulation of protein degradation, or proteolysis, is ....The future of cancer therapy lies in the tailoring of treatment to the characteristic of individual tumour. We have previously identified a subset of breast tumours that are characterised by the presence of large excess of proteins called D-type cyclins. Similar overexpression of cyclin D1 has been shown to lead to the development of cancer in mammary gland in animal models. In normal cells, D-type cyclins are degraded rapidly, therefore the regulation of protein degradation, or proteolysis, is crucial in preventing the accumulation of D-type cyclins. In the subset of breast cancers we have identified, D-type cyclin proteolysis is defective. We, and others, have obtained evidence for the involvement of the SKP2 gene in the proteolysis of D-type cyclins. SKP2 has also been shown to be required for the proteolysis of another important protein, called p27. In the clinic, accumulation of p27 in tumours is used as a good prognostic indicator. However, some exceptions have been found where the accumulation of p27 correlates with aggressive tumours. As D-type cyclins are able to counteract the effect of p27, we hypothesise that the aggressive behaviour of these tumours is due to the simultaneous accumulation of D-type cyclins and that this is due to a mutation in the SKP2 gene. The experiments described in this proposal are designed to test this hypothesis. As the choice of treatment is affected by the interpretation of p27 levels, the results obtained from this study may have a direct impact in the clinic.Read moreRead less
Viral Triggers Of Autoimmunity And Type 1 Diabetes: A Prospective Study Of At Risk Children
Funder
National Health and Medical Research Council
Funding Amount
$475,106.00
Summary
We are studying the role of viruses in causing type 1 (insulin dependent) diabetes. By following babies from birth, we can see whether early signs of damage to the body's insulin producing cells results from infection with particular viruses. We will study the genes and other features of these viruses to help us understand why they cause diabetes, and how they relate to other factors such as diet and vitamin D. The results may provide valuable information for the future prevention of diabetes.
Does A Whey-Protein And Vitamin D Enriched Drink Enhance The Health Benefits Of The Lift For Life® Resistance Training Program In Older Adults With Type 2 Diabetes?
Funder
National Health and Medical Research Council
Funding Amount
$572,023.00
Summary
Since type 2 diabetes is projected to affect over 1.8 million Australians by 2025, there is an urgent need to identify safe and acceptable population-based strategies to improve glucose metabolism and related cardiometabolic risks factors which are common in this population. This study will examine whether increased dietary protein and vitamin D treatment can enhance the effects of resistance training on body composition, glycaemic control and cardiometabolic risk factors in older adults with ty ....Since type 2 diabetes is projected to affect over 1.8 million Australians by 2025, there is an urgent need to identify safe and acceptable population-based strategies to improve glucose metabolism and related cardiometabolic risks factors which are common in this population. This study will examine whether increased dietary protein and vitamin D treatment can enhance the effects of resistance training on body composition, glycaemic control and cardiometabolic risk factors in older adults with type 2 diabetes.Read moreRead less
Investigating Low Sun Exposure And Other Possible Early Life Determinants Of Type 1 Diabtes Mellitus
Funder
National Health and Medical Research Council
Funding Amount
$342,795.00
Summary
Type 1 diabetes mellitus is becoming more common among Australian children. The project explores aspects of the modern child's environment that may increase the risk of type 1 diabetes. In particular it aims to assess whether very low sun exposure in early life is adverse. Low sun exposure may be adverse because sun exposure -derived vitamin D is vital for the developing child's immune system. We need to know what level of sunlight and vitamin D children need to prevent disease.
The Role Of Phospholipase D In Regulating Insulin Secretion
Funder
National Health and Medical Research Council
Funding Amount
$509,267.00
Summary
Insulin, secreted appropriately by the b-cell of the pancreatic islets of Langerhans, regulates blood glucose levels through its effects on various tissues throughout the body. Precise control of insulin secretion from the pancreatic b-cell into the blood is therefore vital for accurate glucose homeostasis. Type II Diabetes Mellitus is caused by the inability of pancreatic b-cells to respond adequately to changes in blood glucose. In the last 18 months we have determined that the enzyme phosphol ....Insulin, secreted appropriately by the b-cell of the pancreatic islets of Langerhans, regulates blood glucose levels through its effects on various tissues throughout the body. Precise control of insulin secretion from the pancreatic b-cell into the blood is therefore vital for accurate glucose homeostasis. Type II Diabetes Mellitus is caused by the inability of pancreatic b-cells to respond adequately to changes in blood glucose. In the last 18 months we have determined that the enzyme phospholipase D (PLD) plays an essential role in distally coordinating signals leading to accurately regulated insulin secretion from the pancreatic b-cell. Through this proposal we now aim to define the signalling pathways upstream of PLD and identify the mechanism downstream that allows PLD activity to regulate insulin secretion. We aim to use a combination of established and novel, biochemical and cell biological, approaches to characterize the role PKC alpha and beta isoforms and the small GTPase cdc42 may have in controlling PLD mediated insulin release. We will also use a variety of cell biological approaches to identify why, where, and when PLD activation is required for appropriate insulin secretion. We will also correlate these observations with the role the cell cytoskeleton may have in mediating PKC, cdc42 and-or PLD effects. In particular we aim to use a state-of-the-art microscope facility recently established at the Garvan Institute to achieve these aims. In doing this we will gain new insights into the pathways determining how insulin is released into the bloodstream, further define cellular processes common to all vesicular trafficking events and also identify potential targets for pharmacological intervention in the disease Diabetes.Read moreRead less
Autocrine Vitamin D Metabolism, Activity And Bone Health
Funder
National Health and Medical Research Council
Funding Amount
$459,270.00
Summary
This project will provide the detailed understanding of the activities of vitamin D within the bone microenvironment and offers the exciting prospect of elucidating the mechanistic reasons for maintaining an adequate vitamin D status in relation to the prevention of osteoporotic hip fractures. Thus, this project has great potential to improve community health by being able to recommend vitamin D supplementation made on the basis of maintaining normal bone cell function.
Vitamin D And Genetic Susceptibility In Multiple Sclerosis
Funder
National Health and Medical Research Council
Funding Amount
$122,714.00
Summary
Vitamin D3 levels appear to predict clinical status in multiple sclerosis. The reasons for this are unclear, but may be linked to the effect of the Vitamin D Receptor (VDR) on a subset of immune cells. This project aims to identify key genes which are regulated by this receptor, by using specific gene sequencing technologies combined with knowledge of the genes which confer risk of developing MS. This may help to identify the molecular pathways underlying MS and potential treatment strategies.