A Novel Intracellular Roadblock To Cobalamin Utilization In Ageing And Alzheimer�s Disease
Funder
National Health and Medical Research Council
Funding Amount
$11,304.00
Summary
Vitamin B12 is required for red blood cell formation, DNA synthesis and normal neurological function. B12 deficiency contributes to age-related cognitive decline and Alzheimer�s disease. This research will provide important new information regarding the ageing process and the impact that brain changes associated with ageing and Alzheimer's disease have on B12 metabolism. It will provide important information related to the therapeutic potential of B12.
Intracellular Cholesteryl Ester Hydroperoxides And Hydroxides- Their Metabolism And Their Modulation Of Cell Function
Funder
National Health and Medical Research Council
Funding Amount
$182,029.00
Summary
Atherosclerosis is the disease which causes narrowings in arteries underlying such serious medical conditions as heart attack and stroke. A key component in the formation of atherosclerotic narrowings is the accumulation of fat-filled cells called foam cell macrophages in artery walls. Our study investigates the nature of the fats that macrophages accumulate, and how mild modification of these fats changes the metabolism of the macrophage. Cholesterol circulates in the blood stream as specialise ....Atherosclerosis is the disease which causes narrowings in arteries underlying such serious medical conditions as heart attack and stroke. A key component in the formation of atherosclerotic narrowings is the accumulation of fat-filled cells called foam cell macrophages in artery walls. Our study investigates the nature of the fats that macrophages accumulate, and how mild modification of these fats changes the metabolism of the macrophage. Cholesterol circulates in the blood stream as specialised particles called lipoproteins. The lipoprotein containing most of the cholesterol is low density lipoprotein (LDL), so-called bad cholesterol. LDL is the main source of fat that accumulates in the artery wall in atherosclerosis. When in the artery wall, it is taken up by macrophages which develop a foamy appearance. The accumulation of LDL fats within macrophages is greatly enhanced by the prior modification of LDL. The most well known of these modifications is oxidation- a chemical process of fat spoilage as occurs with rancid butter. Mild oxidation of LDL is well known to occur in human atherosclerosis. However, the ability of macrophages to accumulate the products of mild oxidation has never been established. We have recently discovered that the lipid products of mild oxidation of LDL can build up in macrophages. We achieved this by developing a new system of feeding oxidised LDL to macrophages. Surprisingly, not only could these lipid oxidation products be internalised by the cells, but they progressively accumulated over time, and caused major disturbances in the ability of macrophages to clear ordinary fats inside the cell. This means that mild oxidation of LDL can cause secondary damage inside the macrophage, which is far greater than had previously been realised. This project investigates precisely how the oxidised LDL is metabolised by macrophages and how it disturbs other cell functions.Read moreRead less
Studies Of A Novel Manganese Transporter In Lysosomes And Its Implications In Niemann-Pick Type-C Disease
Funder
National Health and Medical Research Council
Funding Amount
$527,036.00
Summary
Niemann-Pick type-C disease is a devastating disease affecting child central nervous system. It is due to too much build up of cholesterol in the lysosomal compartment of cells. Recent studies indicate that bivalent cations are involved in the development of the disease. We recently discovered a manganese transporter in the lysosomal compartment and its interaction of the a protein that causing the disease. We will elucidate how manganese transporter controls trace metal balance and may prevent ....Niemann-Pick type-C disease is a devastating disease affecting child central nervous system. It is due to too much build up of cholesterol in the lysosomal compartment of cells. Recent studies indicate that bivalent cations are involved in the development of the disease. We recently discovered a manganese transporter in the lysosomal compartment and its interaction of the a protein that causing the disease. We will elucidate how manganese transporter controls trace metal balance and may prevent the disease.Read moreRead less
Role Of The Lysosomal Protein SCARB2 In Kidney Disease
Funder
National Health and Medical Research Council
Funding Amount
$475,658.00
Summary
Loss of protein in the urine is one of the most important things that happens before the kidneys fail. Losing protein seems to damage the kidneys, but we are still not sure how it happens in most people. We are studying the 'waste management system' of cells, that enables them to get rid of proteins that are no longer required. We have some evidence that this system is abnormal in inherited proteinuria and now want to find out if this is also a problem in more common diseases.
Mechanisms Of Proteolysis Of Proteins Containing Oxidised Amino Acids
Funder
National Health and Medical Research Council
Funding Amount
$406,320.00
Summary
There is evidence that during ageing, and age-related diseases, proteins which have been chemically modified by oxidation accumulate in the body, and may have deleterious effects. Oxidation of proteins is a process akin to that by which fats go rancid. It has been demonstrated by the applicants to be an important process in formation of cataracts, and in development of the blood vessel disease, atherosclerosis, which is responsible for most heart attacks and stroke. Other important age-related d ....There is evidence that during ageing, and age-related diseases, proteins which have been chemically modified by oxidation accumulate in the body, and may have deleterious effects. Oxidation of proteins is a process akin to that by which fats go rancid. It has been demonstrated by the applicants to be an important process in formation of cataracts, and in development of the blood vessel disease, atherosclerosis, which is responsible for most heart attacks and stroke. Other important age-related diseases, such as Alzheimer s disease and other neurological disorders, are also claimed to be associated with deranged protein oxidation, and accumulation of oxidised products. There is clear evidence that certain defensive mechanisms, such as those acting to remove invading organisms and clear wounds, are also associated with an enhanced production of oxidised proteins. Perhaps the most important component of defense against oxidised proteins is their removal by complete breakdown to constituent components, and excretion. Normally, the machinery for breakdown of proteins is in vast excess over the required rate of degradation. However, clearly in these conditions of accumulation of oxidised proteins, this is no longer the case, or no longer suffices. Mechanisms by which oxidised proteins are degraded are poorly understood, and quite controversial. Therefore, the present studies bring to bear a new approach to studying this issue, which has been developed by the applicants. The aim is to reveal mechanisms involved in the breakdown of proteins containing oxidised amino acids, both in cellular systems, and in vivo. Such an understanding may allow us to envisage how to remove oxidised proteins by therapeutic means and therefore interfere with the development of age-related diseases such as Alzheimer s disease and cataract formation and the diseases of the blood vessels associated with attack and stroke.Read moreRead less
MECHANISMS OF PATHOLOGY AND NEW THERAPEUTIC OPTIONS FOR GAUCHER DISEASE AND OTHER LIPIDOSES
Funder
National Health and Medical Research Council
Funding Amount
$439,500.00
Summary
The sphingolipidoses are a subgroup of the more than 45 genetic disorders known collectively as lysosomal storage disorders (LSD). As a result of the deficiency of specific enzymes or proteins involved in the breakdown of sphingolipids (fats), there is an accumulation of this material in affected cells. These diseases can affect liver, spleen, kidney, bone and the central nervous system. Gaucher disease is the prototype for the sphingolipidoses and, in this project, we will use this disease as a ....The sphingolipidoses are a subgroup of the more than 45 genetic disorders known collectively as lysosomal storage disorders (LSD). As a result of the deficiency of specific enzymes or proteins involved in the breakdown of sphingolipids (fats), there is an accumulation of this material in affected cells. These diseases can affect liver, spleen, kidney, bone and the central nervous system. Gaucher disease is the prototype for the sphingolipidoses and, in this project, we will use this disease as a model for this group of disorders. Gaucher disease in the most prevalent LSD with an incidence of 1:56,00 births, worldwide there are approximately 2300 affected individuals born each year. Enzyme replacement therapy (ERT) for Gaucher disease has been successful in the treatment of the non-neuropathic form of the disease. However ERT is expensive ($200,000-400,000 pa). There are approximately 50 Australian patients undergoing ERT at a cost of at least $10 million per annum. However, due to the high cost of treatment, many people do not qualify for ERT, despite having serious medical problems. Worldwide, there are approximately 4000 people currently receiving ERT for Gaucher disease at a total drug cost of over $1.0 billion pa. However, based on birth rates and life expectancies there are over 80,000 Gaucher patients in the world. With the current cost of ERT it is likely that over 90% of these will never receive ERT. If therapy is to be made available for the majority of affected individuals, cheaper alternatives will be required. In this project we will use cellular models of Gaucher disease to study the processes leading to the disease and to develop alternative, cheaper therapies for this disease and other types of sphingolipidoses, for which no therapies currently exist.Read moreRead less
How The Intracellular Pathogen Coxiella Burnetii Manipulates Host Small GTPases To Facilitate Disease
Funder
National Health and Medical Research Council
Funding Amount
$534,510.00
Summary
This study explores how the bacterium Coxiella burnetii causes the serious infectious disease Q fever. Coxiella is a potential biological weapon because it is stable in the environment and few organisms are required to cause disease. Coxiella is able to manipulate human cells to replicate in a unique location within the cell but little is known about how they do this. Here we will study the host proteins that are important during infection and how Coxiella manipulates these factors to facilitate ....This study explores how the bacterium Coxiella burnetii causes the serious infectious disease Q fever. Coxiella is a potential biological weapon because it is stable in the environment and few organisms are required to cause disease. Coxiella is able to manipulate human cells to replicate in a unique location within the cell but little is known about how they do this. Here we will study the host proteins that are important during infection and how Coxiella manipulates these factors to facilitate intracellular replication.Read moreRead less
Defining Pathogenic Mechanisms Of Intracellular Bacteria
Funder
National Health and Medical Research Council
Funding Amount
$494,691.00
Summary
This study explores how the bacterium Coxiella burnetii causes the serious infectious disease Q fever. Coxiella is a potential biological weapon because it is very stable in the environment and few organisms are required to cause disease. Coxiella is able to commandeer human cells to replicate in a specialized vacuole but little is understood about how they do this. We will examine the virulence factors of Coxiella and investigate how they allow the bacteria to replicate inside human cells.