Many drugs modulate the function of proteins imbedded in cell membranes. Extensive research has been undertaken to better understand drug interactions with these proteins to improve drug therapies, but there has been relatively little progress in understanding the role of the cell membrane. This project will investigate how the cell membrane influences protein function and then use this information to develop novel drugs for the treatment of neurological disorders.
The proposed research project involves a fundamental biochemical and biophysical investigation of a protein (ABCA4) intimately involved in the visual process. The precise role of ABCA4 in vision has not yet been elucidated, although evidence suggests a role as a lipid translocase in the retinal regenerative pathway. Our primary objective is to provide direct evidence for this putative role.
Functional And Structural Studies Of A Glycosyltransferase Essential For Complex Glycolipid Biosynthesis In Mycobacteria
Funder
National Health and Medical Research Council
Funding Amount
$508,838.00
Summary
Tuberculosis (TB) kills more than three million people each year while the causative bacterial species, Mycobacterium tuberculosis, infects one-third of the entire human population. An alarmingly high rate of TB exists in Australia's indigenous population. This proposal aims to identify and characterise essential processes involved in synthesis of the outer coat of the bacterium which are potential targets for new drugs for the treatment of this devastating disease.
Development Of Bacterial Mechanosensitive Channels As Nanodevices In Liposome Systems For Targeted Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$502,341.00
Summary
Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and a ....Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and administer potent and even highly toxic drugs such as the anthracyclines, Doxorubicin and Daunorubicin (clinically approved anti-cancer treatments), Amphotericin B (fungal disease therapy) and Taxol (cancer therapy).The focus of this project is to incorporate nanovalves into these drug delivery systems, in the form of bacterial mechanosensitive (MS) channels, to facilitate the controlled and rapid release of encapsulated drugs at targeted tumours or disease tissues. The successful completion of this project represents a significant advance on existing liposomal drug delivery systems because MS channels open and release the drug into or onto the target cell immediately following liposome binding. Liposomal drug delivery systems offer the additional advantages that they concentrate the drug inside the target tissue, thereby increasing its efficacy; reduce the exposure of healthy cells to toxic drugs; and increase safety to patients through loading site-specific drugs into site-directed liposomes. Specifically this project will develop: 1. Liposome formulations in which the MS channels are closed, but poised to open upon binding to the target cell. 2. Customised MS channels designed to optimize controlled release. 3. Structural information that will assist in the treatment of channelopathies linked to MS channels, i.e. diseases resulting from defects in MS ion channel function (e.g. muscular dystrophy, cardiac arrhythmias, autosomal-dominant polycystic kidney disease).Read moreRead less
Mechanosensitive Channels: Antimicrobials, Channelopathies And Nanovalves For Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$673,953.00
Summary
Liposomal drug delivery systems (LDDS) are one of the most advanced particulate drug carriers in modern medicine. The ultimate goal of this project is to optimize a nanotechnology approach for improved control of therapeutic drug delivery for chemotherapy. The approach is using bacterial mechanosensitive channel MscL designed to act as a molecular nanovalve for localised drug release.
A Novel Patch-fluorimetry Technique For Investigating Structural Changes During Gating Of Mechanosensitive Ion Channnels
Funder
National Health and Medical Research Council
Funding Amount
$387,018.00
Summary
Membrane proteins, especially membrane channels play an important role in regulating the flow of substances across the cell. Dysfunction in these channels can lead to a variety of diseases. Thus approximately 60% of drug development is targeted against such proteins. In our research, we are looking at membrane channels found in bacteria. Understanding the function of these channels will help us develop novel anti-bacterial agents. It will also aid to understand a role of ion channels in disease.
The Role Of Seipin In Lipid Metabolism And Adipogenesis
Funder
National Health and Medical Research Council
Funding Amount
$397,749.00
Summary
The prevalence of obesity and its related disorders has reached an alarming level in Australia and other developed countries. Obesity is characterized by accumulation of fully-differentiated adipocytes loaded with lipid droplets (LDs). Therefore, understanding the cellular dynamics of LDs and the molecular mechanisms of adipogenesis (adipocyte differentiation) is of crucial importance in our battle against obesity. Our proposed study will help undertand the mechnisams of obesity.
Elucidating Metabolic Dysregulation In Alzheimer’s Disease: Profiling The Peripheral Immune Cell Lipidome To Unravel Pathological Mechanisms.
Funder
National Health and Medical Research Council
Funding Amount
$645,205.00
Summary
Both the immune system and lipid metabolism have been identified to be important in Alzheimer’s disease (AD). With the failures of all clinical trials attempting to treat AD, we seek to determine a way to both better diagnose individuals with AD and to identify people at increased risk. This project uses a novel profiling technique to characterise the lipid composition of immune cells to diagnose, predict risk, monitor the disease and to identify potential disease modifying therapeutic targets.
Lipoprotein Metabolism And Mutations Of The APOB Gene Causing Familial Hypobetalipoproteinaemia
Funder
National Health and Medical Research Council
Funding Amount
$396,179.00
Summary
Cardiovascular disease is an increasing problem in Australia, however, the cause of atherosclerosis is incompletely understood. A protein, known as apolipoprotein (apo) B, plays a central role in lipoprotein metabolism. Elevated levels of apoB are characteristic of many forms of hypercholestrolaemia. Familial combined hyperlipidaemia and polygenic hypercholesterolaemia are two common inherited disorders of lipoprotein metabolism that are characterised by elevated apoB levels in the blood and ear ....Cardiovascular disease is an increasing problem in Australia, however, the cause of atherosclerosis is incompletely understood. A protein, known as apolipoprotein (apo) B, plays a central role in lipoprotein metabolism. Elevated levels of apoB are characteristic of many forms of hypercholestrolaemia. Familial combined hyperlipidaemia and polygenic hypercholesterolaemia are two common inherited disorders of lipoprotein metabolism that are characterised by elevated apoB levels in the blood and early atherosclerosis. In contrast, familial hypobetalipoproteinemia is a rare inherited disorder of lipoprotein metabolism characterised by very low levels of cholesterol and apoB in the blood and resistance to atherosclerosis and cardiovascular disease. The focus of this research project is to explore the regulation of apoB metabolism using individuals from unique families with familial hypobetalipoproteinaemia. First, we will determine and characterise the alterations in the APOB gene causing the low cholesterol levels in families with familial hypobetalipoproteinaemia. Second, we will determine if these apoB alterations affect the production and-or clearance of blood fats, or lipoproteins in affected individuals, when compared to controls, by performing metabolic studies. The proposed human in vivo metabolic studies will lead to a better understanding of the mechanism(s) involved in the assembly, secretion, transport, and clearance of plasma apoB-containing lipoproteins. Furthermore, these studies may reveal new protective mechanisms and potentially aid in the development of strategies to suppress over-production of apoB-containing lipoproteins in reciprocal conditions such as familial combined hyperlipidaemia or polygenic hypercholesterolaemia.Read moreRead less