An AMPK Myristoyl Switch Controls AMP Mediated Metabolic Stress Signaling
Funder
National Health and Medical Research Council
Funding Amount
$524,820.00
Summary
This project is investigating an enzyme called AMP-activated protein kinase that plays a pivotal role in controlling how our bodies regulate energy metabolism in response to exercise and diet. Improved understanding of how this enzyme is regulated may provide new therapeutic methods for mimicking the beneficial effects of diet and exercise to treat multiple metabolic diseases including obesity, Type 2 diabetes and cardiovascular disease.
Characterization Of The Phosphoinositide 5-phosphatase SKIP.
Funder
National Health and Medical Research Council
Funding Amount
$505,523.00
Summary
Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzym ....Growth factors and insulin stimulate a complex array of signals inside the cell, which are important for both cell survival and metabolism. A central intracellular signaling enzyme that initiates lipid messages that promote glucose uptake into the cell and promote cell survival is that generated by the PI3-kinase. This enzyme has increased activity in many cancers, and is also important in diabetes when the enzyme may be suppressed. Our grant proposes to investigate the function of another enzyme called SKIP which acts within the cell to oppose the functions of the PI3-kinase. Several lines of evidence indicate SKIP may be important in both development and cancer. SKIP has been identified as a putative candidate gene for a developmental disorder known as Miller Dieker syndrome. This disease is associated with facial and significant brain abnormalities. In addition the SKIP gene is located on a chromosome that is frequently deleted in breast and colon cancer. SKIP is an enzyme that functions to remove phosphate molecules from PI3-kinase signaling molecules. SKIP has been shown to prevent glucose uptake into the cell by breaking down PI3-kinase signals. We have recently demonstrated SKIP phosphatase activity can be inhibited by binding to another protein called suppressor of death domains (SODD). We plan to investigate the effects this complex has on SKIP enzyme activity, and how this complex plays a role in regulating PI3-kinase signals that promote glucose uptake. Secondly, we plan to investigate the function of SKIP in an intact animal by making mice which lack SKIP(knock out mice). Given SKIP is implicated in a developmental syndrome and insulin signaling, we can delineate the functional significance of SKIP and the molecular pathways regulated by this enzyme.Read moreRead less
Novel Upstream Regulatory And Down-stream Signaling Mechanisms Of The Src-family Protein Kinases
Funder
National Health and Medical Research Council
Funding Amount
$363,639.00
Summary
Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by thei ....Normal cell growth and division are governed by the balanced action of two groups of enzymes - the enzymes encoded by the proto-oncogenes (precursors of cancer-causing genes) and the tumour suppressor genes. Abnormalities in the regulation of these enzymes cause cancer. Indeed, over-stimulation of a group of proto-oncogenic enzymes called the Src-family kinases (SFKs) is the major contributing factor to most human cancers. In this application, we propose to study how inactivation of SFKs by their native inhibitor CHK suppresses cancer formation and how over-stimulation of SFKs causes cancer. Exactly how CHK inactivates SFKs remains unclear. Recently, we discovered a novel mechanism employed by CHK to inhibit SFKs. In this mechanism, CHK binds to SFKs tightly and the binding alone is sufficient to completely shut down SFK activity. As this novel inhibitory mechanism of CHK can be exploited for the development of synthetic SFK inhibitors for cancer treatment, we propose to unravel how CHK tightly binds to SFKs and how the binding inhibits the cancer-promoting activity of SFKs. How over-stimulation of SFKs induces the development of human cancer has been an important outstanding question in cancer research. Recently, we and two groups of researchers in Texas achieved breakthroughs in answering this question. The Texan groups discovered that the over-stimulated SFKs cause cancer by shutting down the anti-tumour activity of a tumour suppressor called PTEN. We complemented their findings by discovering how SFKs shut down PTEN activity - SFKs shut down PTEN activity by a chemical modification process called phosphorylation. In this application, we propose to study how SFKs modify PTEN and how phosphorylation shuts down the tumour suppressor activity of PTEN. In summary, our studies will benefit the development of two types of anti-cancer therapeutics: (i) those mimicking CHK binding and inhibition of SFKs, and (ii) those interfering with phosphorylation of PTEN by SFKs.Read moreRead less
Wave slam on high speed wave piercing catamaran ferries in large seas. Australia has taken a pioneering lead in the design of high speed multi-hull ferries and continues to extend their speed, range and payload performance. Design leadership and the technology which supports it are crucial to maintaining the existing large share of the international market for such vessels. Recently freight and military transport vessels have been exposed to much more severe wave conditions than passenger vessel ....Wave slam on high speed wave piercing catamaran ferries in large seas. Australia has taken a pioneering lead in the design of high speed multi-hull ferries and continues to extend their speed, range and payload performance. Design leadership and the technology which supports it are crucial to maintaining the existing large share of the international market for such vessels. Recently freight and military transport vessels have been exposed to much more severe wave conditions than passenger vessels and this has increased the need for improved prediction of structural loads due to waves. This project directly addresses that need by computation and model testing validation. The industry is a significant export earner and employer within Australia and so the project directly underpins those national benefits. Read moreRead less
Asymmetric and nonlinear unsteady loads on high speed ferries. Large high speed catamarans are expanding their domain of application from coastal passenger routes to ocean freight and military service. This is shifting operability criteria from motions and passenger discomfort to structural load limitations in severe wave environments. This project investigates large wave structural load prediction. Large waves lead to strongly non-linear responses, invalidating many methods of analysis. Predict ....Asymmetric and nonlinear unsteady loads on high speed ferries. Large high speed catamarans are expanding their domain of application from coastal passenger routes to ocean freight and military service. This is shifting operability criteria from motions and passenger discomfort to structural load limitations in severe wave environments. This project investigates large wave structural load prediction. Large waves lead to strongly non-linear responses, invalidating many methods of analysis. Prediction of loads on the transverse structure is also not possible with many prediction methods. This project will develop and validate by experiment fully time domain computational methods for the prediction of asymmetric structural loads due to large wavesRead moreRead less
A hybrid approach to predict the structure-borne noise transmission in ship structures using a waveguide method and Statistical Energy Analysis. The prediction of structure-borne noise transmission in large welded ship structures is required, in order to design maritime vessels with greater ship power and reduced weight, without increasing the noise levels. The aim of this project is to develop a hybrid approach for structural dynamic analyses using an analytical waveguide method and Statistical ....A hybrid approach to predict the structure-borne noise transmission in ship structures using a waveguide method and Statistical Energy Analysis. The prediction of structure-borne noise transmission in large welded ship structures is required, in order to design maritime vessels with greater ship power and reduced weight, without increasing the noise levels. The aim of this project is to develop a hybrid approach for structural dynamic analyses using an analytical waveguide method and Statistical Energy Analysis. The theoretical estimation and associated experimental measurement of the SEA parameters (modal density, coupling and internal loss factors) form the basis for the hybrid approach. The outcomes will result in improved predictive techniques for dynamic analyses of large complex resonant structures.Read moreRead less
Phosphatase Regulators Mediate Long-term Changes In Presynaptic Terminals
Funder
National Health and Medical Research Council
Funding Amount
$984,163.00
Summary
The strength of communication between each nerve cell in the brain depends on how active that nerve cell has been. This enables the brain to be adaptable and is a way for the brain to set up circuits that underlie how we learn and remember. More or less release of chemical messengers (neurotransmitters) into nerve cell junctions changes the strength of nerve cell communication. We have discovered a new chemical signalling pathway controlling neurotransmitter release.
Cardiovascular Effects Of Enhanced Leptin Signalling
Funder
National Health and Medical Research Council
Funding Amount
$1,200,972.00
Summary
Leptin treatment causes weight loss, but leptin also increases blood pressure. We wish to determine if increasing leptin signalling, by modifying signal transduction pathways within leptin sensitive cells in the brain, can reduce weight without increasing blood pressure.