Lipid Trafficking At Membrane Contact Sites: The Role Of Oxysterol-Binding Protein-Related Protein 5 And 8 (ORP5 And ORP8)
Funder
National Health and Medical Research Council
Funding Amount
$466,400.00
Summary
Abnormal subcellular lipid distribution is associated with a number of common diseases including cancer, cardiovascular disease, and Alzheimer’s disease. The overall aim of this proposal is to identify and characterize new molecules that regulate the transport of lipids between different cell membranes. Results from the proposed studies will help developing novel therapeutic agents against common human diseases.
Atherosclerosis is the disease which narrows arteries and causes heart attacks and stroke. It is one of the major causes of death in Australia. Although certain treatments, such as lowering blood cholesterol levels, reduce the incidence of atherosclerosis, current motality rates from this disease indicate that there is still a great need to improve our understanding and treament of the condition. In the development of atherosclerosis, some of the cells in the vessel wall accumulate large deposit ....Atherosclerosis is the disease which narrows arteries and causes heart attacks and stroke. It is one of the major causes of death in Australia. Although certain treatments, such as lowering blood cholesterol levels, reduce the incidence of atherosclerosis, current motality rates from this disease indicate that there is still a great need to improve our understanding and treament of the condition. In the development of atherosclerosis, some of the cells in the vessel wall accumulate large deposits of cholesterol. These cells are macrophages, derived from circulating white blood cells that have migrated into the vessel wall. Normally these cells are able to efficiently export excess cholesterol, but this process seems to fail in atherosclerosis. This project will study the molecular mechanism for cholesterol export from macrophages, concentrating on a the mechnisms by which recently identified cholesterol pumps operate. These are located in cell membranes, including at the cell surface, which is the site at which cholesterol is transferred to acceptors such as HDL and apoAI. By understanding how these pumps work, and how their activities are controlled, we will be better able to devise ways to increase their efficiency in atherosclerosis, and so to prevent the tissue cholesterol accumulation that drives this disease.Read moreRead less
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
The Role Of Seipin In Adipocyte Development And Lipid Droplet Formation
Funder
National Health and Medical Research Council
Funding Amount
$376,258.00
Summary
The prevalence of obesity and its related disorders has reached an alarming level in Australia and other developed countries. Obesity is characterized by the accumulation of fully-differentiated adipocytes loaded with lipid droplets (LDs). We aim to characterize seipin, which regulate both lipid droplet formation and adipocyte differentiation. Results from our proposed studies may offer novel therapeutic strategies against human obesity.
Unravelling A New Fatty Acid Pathway Involved In Neuroexocytosis And Memory
Funder
National Health and Medical Research Council
Funding Amount
$539,631.00
Summary
This proposal build on the establishment by our laboratory of the assay capable of detecting free fatty acids, with great accuracy and sensitivity. Using this assay we have uncovered a completely new pathway highlighting the production of saturated free fatty acids linked to learning and memory. We will fully define how this pathway is regulated in the brain.
The Role Of Phosphatidic Acid In Lipid Storage And Obesity
Funder
National Health and Medical Research Council
Funding Amount
$496,169.00
Summary
The prevalence of obesity and its related disorders has reached an alarming level in Australia and other developed countries. Obesity is characterized by the accumulation of fully-differentiated adipocytes loaded with lipid droplets (LDs). We aim to examine the role of phosphatidic acid in lipid droplet formation and adipocyte differentiation. Results from our proposed studies may offer novel therapeutic strategies against human obesity and type II diabetes.
Elucidating The Mechanism And Function Of Extracellular Vesicle Formation During Cell Death
Funder
National Health and Medical Research Council
Funding Amount
$318,768.00
Summary
In humans, billions of cells will die daily as part of normal turnover in various organs. It is vital that dying cells are rapidly removed as their accumulation has been linked to autoimmunity and inflammation. To aid efficient removal of dead cells, dying cells can disassemble into smaller fragments for neighbouring cells to engulf. We aim to understand the machinery that control how dying cells can disassemble into smaller pieces and their function in efficient cell clearance and autoimmunity.
Long Chain Omega-3 Polyunsaturated Fatty Acids and Heart Health in Humans. The primary aims of the project is to assess the effect of DHA rich tuna oil on cholesterol carrying lipoproteins and to determine a quicker method in assessing someone's omega-3 status. The expected outcomes include the determination of: 1) the most appropriate blood sample and a rapid test and for evaluating the omega-3 status; 2) the minimum dose of tuna oil required which will not only improve a person's omega-3 statu ....Long Chain Omega-3 Polyunsaturated Fatty Acids and Heart Health in Humans. The primary aims of the project is to assess the effect of DHA rich tuna oil on cholesterol carrying lipoproteins and to determine a quicker method in assessing someone's omega-3 status. The expected outcomes include the determination of: 1) the most appropriate blood sample and a rapid test and for evaluating the omega-3 status; 2) the minimum dose of tuna oil required which will not only improve a person's omega-3 status but also improve their plasma lipid profile and hence reduce their overall risk for cardiovascular disease (CVD); and 3) the use of the Omega-3 Index by medical practitioners. The significance is the increased knowledge of the health benefits of DHA rich tuna oil and that a new CVD risk marker will be generally accepted.Read moreRead less