Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insu ....Following a meal glucose circulates in the blood and is taken up into cells via movement of an intracellular glucose transporter from the inside of the cell to fuse with the cell membrane and subsequent transfer of the glucose into the cell. This process is triggered by insulin. One of the commonest diseases resulting from a failure of this cellular process is diabetes. A common form of diabetes which occurs in many adults in Australia results from insulin resistance, whereby the effects of insulin are diminished and cells become increasingly unable to uptake glucose. Recent studies have demonstrated that a novel enzyme known as SHIP-2 may play a role in regulating insulin action in cells. Deletion of SHIP-2 in mice results in these animals have increased sensitivity to insulin, low blood glucose levels, and a greatly enhanced ability to take up glucose in cells in response to low dose insulin. Our laboratory has been working on the cellular mechanisms regulating SHIP-2 function. We have recently revealed the intracellular location of SHIP-2 and also demonstrated how SHIP-2 is localized in the cell. These studies have shown that SHIP-2, via interactions with other proteins, regulates the actin cytoskeleton immediately beneath the cell membrane and this may be a mechanism for facilitating cellular glucose uptake. This research proposal aims to determine how SHIP-2 facilitates glucose uptake into cells. We will make cell lines and transgenic animals which express high levels of this enzyme and determine the functional consequences on insulin stimulated glucose uptake. Collectively these studies in the long term may facilitate better treatment strategies for diabetic patients.Read moreRead less
Regulation Of SRC-Family And Focal Adhesion Kinase Function
Funder
National Health and Medical Research Council
Funding Amount
$381,338.00
Summary
Cells in our bodies stick to one another and to the cementing material called extracellular matrix surrounding them. An ezyme called focal adhesion kinase (FAK) is a major regulator of cell stickiness. It can catalyze the covalent attachment of a chemical group called phosphate to specific cellular protein. This proposal aims at studying how FAK is regulated by insulin stimulation and how FAK is regulated by a tumour suppressor called PTEN. Results of the study will shed light on how abberration ....Cells in our bodies stick to one another and to the cementing material called extracellular matrix surrounding them. An ezyme called focal adhesion kinase (FAK) is a major regulator of cell stickiness. It can catalyze the covalent attachment of a chemical group called phosphate to specific cellular protein. This proposal aims at studying how FAK is regulated by insulin stimulation and how FAK is regulated by a tumour suppressor called PTEN. Results of the study will shed light on how abberrations in the regulation and PTEN contribute to the development of development defects, heart attack, and the spreading of cancer cells.Read moreRead less
Regulation Of The Tumour Suppressor PTEN By Phosphorylation And Oligomerization
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
The tumour suppressor PTEN is an enzyme involved in controlling cell growth, cell death, and cell migration. PTEN was identified as a tumour suppressor because many tumour cells were found to carry mutations in the PTEN gene that cause the loss of PTEN protein or the loss of PTEN enzyme activity. Hereditary mutations of the PTEN gene are the causes of a rare genetic disease called Cowden's disease. Cowden's disease patients are predisposed to developing skin, thyroid, and breast cancers. In labo ....The tumour suppressor PTEN is an enzyme involved in controlling cell growth, cell death, and cell migration. PTEN was identified as a tumour suppressor because many tumour cells were found to carry mutations in the PTEN gene that cause the loss of PTEN protein or the loss of PTEN enzyme activity. Hereditary mutations of the PTEN gene are the causes of a rare genetic disease called Cowden's disease. Cowden's disease patients are predisposed to developing skin, thyroid, and breast cancers. In laboratory conditions, increasing the abundance of PTEN in tumour cells such as brain and prostate tumour cells can suppress their growth, hence its role as a tumour suppressor. In addition to its role as a tumour suppressor, PTEN controls cancer cell spreading. Although much is known about the involvement of PTEN in cancer formation and the spreading of cancer cells, how PTEN suppresses tumour cell growth and spreading is not fully understood. The enzyme activity of PTEN enhances the removal of a chemical group called phosphate group from proteins and the fat-soluble compounds called phospholipids in the cell membrane. The ability of PTEN to suppress cell growth and spreading is due to its enzyme activity. However, exactly how the enzyme activity of PTEN is regulated is not well understood. In order for PTEN to efficiently enhance the removal of phosphate group from specific cellular proteins and phospholipids, PTEN needs to be located in close vicinity to these proteins and phospholipids. However, exactly how PTEN moves to the locations where these proteins and phospholipids are present remains elusive. This proposal aims at studying the regulation of PTEN enzyme activity and movement inside the cells. Results of the proposed studies will shed new light on how PTEN gene mutations contribute to cancer formation and the spreading of cancer cells and may facilitate the search for the cure of cancers.Read moreRead less
Alzheimer's Disease And Related Disorders: Mechanism Of Tau Pathology In Established And Novel Transgenic Animal Models
Funder
National Health and Medical Research Council
Funding Amount
$423,017.00
Summary
Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We wer ....Alzheimer's disease (AD) is a devastating neurodegenerative disease for which no cure is available. It affects more than 15 million people worldwide. There are estimates that by 2040, approximately 500'000 Australians will suffer from AD, with associated health costs of about 3% of the GDP. AD is characterized by two major brain lesions, beta-amyloid plaques and neurofibrillary tangles (NFTs). The latter contain a protein called tau which is in a fibrillar and highly phosphorylated state. We were the first to establish a transgenic animal model of pre-tangles and, together with Dr. Hutton's laboratory, of NFT formation. We could further show that injections of beta-amyloid into brains of our tau mutant mice enhanced the NFT pathology in these mice. By Functional Genomics we identied genes and proteins, which are induced by tau expression. The specific aim of this proposal is to determine whether oxidative stress enhances the tau pathology in our tau mutant mice and whether distinct brain areas are particularly susceptible to this kind of stress. The reason for addressing this question is twofold: On the one hand, we have found in our mice that reactive oxygen species are increased, secondly it is known that some brain areas in the AD brain are degenerating, whereas others are not. A second aim is to develop novel tau transgenic models where individual interactions of tau with cellular proteins are disturbed. Finally, we want to determine whether the two kinases BMX and FAK and the phosphatase PPV regulate tau phosphorylation in vivo. Together, we hope that our efforts lead to a better understanding of the pathogenic mechanisms in AD and related disorders. As pathocascades are likely to be shared between a range of diseases, these findings may also contribute to other fields of research, such as Parkinson's disease. Ultimately, these efforts will assist in the development of a safe treatment of AD.Read moreRead less