Mechanisms Of Oxidised Protein Accumulation In Ageing Cells
Funder
National Health and Medical Research Council
Funding Amount
$429,000.00
Summary
Australia has one of the world's most rapidly ageing populations. It is estimated that in 30 years time over 30% of the population will be over 65; many will suffer from a debilitating, age-related disease. The diseases of ageing represent one of the major health challenges this century. Despite their increasing incidence, our understanding of the underlying causes is limited. A common feature is the accumulation of damaged proteins in cells and tissues. Damaged proteins are usually broken down ....Australia has one of the world's most rapidly ageing populations. It is estimated that in 30 years time over 30% of the population will be over 65; many will suffer from a debilitating, age-related disease. The diseases of ageing represent one of the major health challenges this century. Despite their increasing incidence, our understanding of the underlying causes is limited. A common feature is the accumulation of damaged proteins in cells and tissues. Damaged proteins are usually broken down by the cells and replaced, but in many age-related diseases this process fails. The most common source of protein damage is attack by oxygen-derived free radicals. These are by-products of our body's need for oxygen and can originate from atmospheric pollutants. Oxygen rusts metal, makes fat go rancid and can cause irreparable damage to proteins and other biological molecules. Free radical damage contributes to the development of many age-related diseases such as atherosclerosis and neurodegenerative diseases such as Alzheimer's disease. The accumulation of damaged proteins can cause cell death. Our knowledge of the mechanisms by which cells remove proteins damaged by oxygen and the reasons for their accumulation is limited. In this project we will use a novel technique we have developed to generate oxidised proteins in ageing cells. We will identify cellular mechanisms required for the efficient removal of damaged proteins and those mechanisms which fail in ageing cells. We will focus on a group of proteins which protect damaged proteins from aggregating and accumulating and we will examine how we can prevent the accumulation of oxidised proteins by stimulating the body s defence mechanisms. Since the population of Australia is ageing, diseases of ageing are going to consume an increasing amount of the national health budget. A better knowledge of these cellular mechanisms will allow us to design effective prevention and treatment strategies which are at present lacking.Read moreRead less
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
Discovery And Mechanisms Of Host Cell Factors In HIV Uncoating
Funder
National Health and Medical Research Council
Funding Amount
$635,098.00
Summary
HIV entry into the host cell involves release of its capsid, a protein shell protecting the viral genome. The capsid hijacks host proteins to cloak itself from cellular defenses while the cell has evolved sensors that can block viral infection. This proposal aims to discover proteins involved in this arms race between host and virus and decipher how they control capsid disassembly. This insight will help design new drugs against HIV infection and new ways to deliver genes for gene therapies.
Structural And Functional Analysis Of A Cancer-linked Co-regulator Complex
Funder
National Health and Medical Research Council
Funding Amount
$729,571.00
Summary
We seek to understand the mechanisms by which genes are switched on and off throughout our lifetime. A number of multi-component protein machines are involved in this process but their make-up and mechanism of action is not understood. We will investigate the structure and function of one of these machines that has been strongly linked to cancer.
Prion-like Behaviour In Immunity: Super-sized Signalling Platforms?
Funder
National Health and Medical Research Council
Funding Amount
$611,995.00
Summary
Prions have been mostly associated with pathologies but recent discoveries show that prion-like behaviour may be beneficial, enhancing our immune response for example. To test this, we want to systematically explore all human proteins involved in the defence against pathogens, find new prion-like trends and probe their role in the innate immune response.
Structural And Functional Studies On RNA Nuclear Retention Mediated By Paraspeckles: A Novel Gene Regulation
Funder
National Health and Medical Research Council
Funding Amount
$290,978.00
Summary
Dynamic interactions between proteins and nucleic acids are essential process in gene regulation, where aberrant regulation leads to various diseases including cancers. The project aims to examine the interactions between paraspeckle proteins and nucleic acid molecules via determination of the structures of protein-nucleic acid complexes at the atomic level. The results will provide a better understanding of a recently discovered gene regulation mechanism and a basis for new gene therapy.
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 Structural Basis For Glutamate Transporter Function
Funder
National Health and Medical Research Council
Funding Amount
$373,144.00
Summary
Glutamate transporters are vacuum cleaners in the brain that suck the neurotransmitter glutamate into cells. When the glutamate vacuum breaks down or becomes blocked, glutamate levels outside cells increase, leading to cell death in the brain. This process underlies the damage in many brain diseases including Alzheimer’s disease and stroke. The aim of this project is to understand the mechanism of the glutamate vacuum cleaner so we can develop therapeutics to fix it when it breaks down.
Biosensor Based Clinical-decision Support For Patients With Heart Failure
Funder
National Health and Medical Research Council
Funding Amount
$691,933.00
Summary
Heart Failure (HF) is a progressive disease and a major global public health concern. HF accounts for a substantial number of hospitalisations, major healthcare resource utilisation and costs. We aim to engineer biosensor platform to stratify the risk in HF patients will revolutionise current management of HF by providing the cardiologist information to risk stratify patients based on protein signature. This will lead to a substantial paradigm shift in clinical practice.
Assembly And Transport Of Herpes Simplex Virus Within Neurones
Funder
National Health and Medical Research Council
Funding Amount
$475,500.00
Summary
Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transpor ....Herpes simplex virus (HSV) enters the human body via the skin before entering the termini of nerve cell processes. It is transported along these processes to the body of the nerve cell. HSV lies dormant within these nerve cell bodies near the spinal cord in most people. Intermittently the virus reactivates and is transported back down the nerve cell processes to the skin where it causes blisters-ulcers or is shed without causing symptoms. The aim of this grant is to determine how HSV is transported and assemblied within nerve cells at the molecular level. Recent discoveries have shown how virus transport in nerve cells is dependent on interactions between specific viral proteins and cellular motor proteins. Such information on viral transport and assembly mechanisms will allow development of inhibitors of these processes which may be candidates for use as antivirals for control of recurrent herpes simplex. In addition, this information will allow the virus to be exploited for use in gene therapy to introduce DNA into human nerve cells to correct genetic abnormalities.Read moreRead less