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
Developing Anti-Inflammatory Drugs Based On Inhibition Of A Human Enzyme
Funder
National Health and Medical Research Council
Funding Amount
$160,000.00
Summary
Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachid ....Human secretory phospholipases A2 have been associated with inflammatory diseases for many years, yet very few truly potent inhibitors of the human enzymes sPLA2 (isoforms IIa, V or X) are known due to a range of problems relating to the lipid nature of substrates, unavailability of enzymes, enzyme assays that do not correlate with in vivo data. Although there remains controversy about which enzyme is responsible in vivo for degrading membrane phospholipids to inflammatory mediators like arachidonate, PAF, prostaglandins, leukotrienes, etc. there is a consensus that blockade of phospholipid metabolism would represent a major advance on NSAIDs as antiinflammatory agents. No sPLA2-IIa inhibitor is available yet in man. We aim to create an attractive data package showing proof of concept for a potent new type of antiinflammatory drug. This data will give us an improved negotiating position in our commercialisation of a new drug with potential multi-billion dollar markets as diverse as arthritis, asthma, reperfusion injury, organ transplantation and many other currently intractable human ailmentsRead moreRead less
Identification Of Novel Targets For Treatment Of Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$486,873.00
Summary
Hearts respond to stimulation by activation of cell surface receptors. We have found that two very closely related receptors have opposing effects on the heart; one is beneficial and the other promotes disease. The planned studies will investigate exactly what explains this difference. This will identify critical factors that protect or damage the heart and is expected to provide suitable targets for drug development.
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.