Mimetics Of Natural Triggers Of Innate Immunity As Vaccines
Funder
National Health and Medical Research Council
Funding Amount
$241,650.00
Summary
Knowledge of what properties of an antigen allow it to induce an immune response is central to our understanding of how we fight disease and how we can vaccinate effectively against disease. The fact that an antigen is foreign to the host is not in itself sufficient for it to initiate the series of events that must take place in order to activate B and T lymphocytes, the cells involved in immunity. For vaccine purposes, antigens must be delivered with substances called adjuvants to be effective. ....Knowledge of what properties of an antigen allow it to induce an immune response is central to our understanding of how we fight disease and how we can vaccinate effectively against disease. The fact that an antigen is foreign to the host is not in itself sufficient for it to initiate the series of events that must take place in order to activate B and T lymphocytes, the cells involved in immunity. For vaccine purposes, antigens must be delivered with substances called adjuvants to be effective. There is very little known about how adjuvants actually work but many of the highly effective experimental adjuvants contain an immunostimulant which is usually either whole dead bacteria or components of the cell walls of bacteria or other organisms. From evidence emerging in the literature and our own experimental observations, we have begun to understand the requirements for and the chain of events leading to immune response induction. The interaction of certain lipid-containing groups, present on antigens from pathogenic organisms, with a specialised type of cell, the dendritic cell, is a key event in this process. We have designed synthetic mimics of lipid-containing moieties from bacteria and coupled them to unrelated parts of viral proteins. We showed that these lipopeptides can elicit potent anti-viral immune responses and long lived memory responses. The experiments outlined in this proposal will examine the interaction of these and other second generation lipopeptides with dendritic cells. We will determine whether these can bind to particular molecules on the dendritic cell surface to initiate a specific series of signals leading to immune induction and if so we will seek to use different lipid groups to trigger the immune response in different and predictable ways. The outcomes of this work may have a major impact on the design of new vaccines as well as increase our understanding of how the immune system is triggered to respond to invading organisms.Read moreRead less
Strategies For Handling Missing Data In The Development, Validation And Implementation Of Clinical Risk Prediction Tools
Funder
National Health and Medical Research Council
Funding Amount
$451,692.00
Summary
Tools that predict the future outcome of disease are common. Missing data is a problem in studies that develop and validate such tools and affects their validity because simple approaches to dealing with missing data are biased. We will develop statistical methodology in this area and compare the performance of this and other methodologies. Alongside this methodological work we will re-assess existing prediction tools and develop new tools in the areas of cardiac surgery and kidney disease.
PREMOTOR SYMPATHETIC CONTROL OF BLOOD PRESSURE DURING PSYCHOLOGICAL STRESS: HYPOTHALAMUS VERSUS MEDULLA.
Funder
National Health and Medical Research Council
Funding Amount
$153,616.00
Summary
Health and well being depend in large part on a strong and efficient autonomic nervous system. The autonomic nervous system controls blood pressure, heart rate, gastrointestinal function, immune responses and certain forms of pain. Negative emotions can have a strong impact on autonomic function. We have all experienced the sweaty hands, pounding heart and intestinal discomfort when the mail arrives and bad news is expected or when we face a deadline for which we are not prepared. This is known ....Health and well being depend in large part on a strong and efficient autonomic nervous system. The autonomic nervous system controls blood pressure, heart rate, gastrointestinal function, immune responses and certain forms of pain. Negative emotions can have a strong impact on autonomic function. We have all experienced the sweaty hands, pounding heart and intestinal discomfort when the mail arrives and bad news is expected or when we face a deadline for which we are not prepared. This is known as psychological stress and it is usually associated with anxiety. Unfortunately, it is also the most common form of stress in modern urban life. There are clear indications that when these autonomic changes become chronic they can lead to hypertension, weak immune responses and gastric ulcers. In people already suffering from cardiovascular diseases they can also precipitate cardiac and cerebrovascular accidents. Clearly, the link between psychological stress and the autonomic nervous system needs to be explored in more detail. This project looks at the organization of the neural network in the brain and spinal cord that controls these responses. It uses a simple model of psychological stress in the conscious rat and recent non invasive techniques to record blood pressure and look at neuronal activity. We think that we have identified a group of neurons that may be controlling very specifically this response. It is located in the hypothalamus. The aim of this project is to further test the role of these neurons and find out what is controlling them. They will also be compared to another group of neurons that also controls blood pressure but apparently not in relation to psychological stress. The possibility that the cardiovascular response to psychological stress might be mediated by a specific group of neurons in the brain is a very exciting finding. It could lead to new therapeutic applications for acting against the short and long term effects of stress.Read moreRead less
Inhibition Of Fear Memories By Extinction: Neural Substrates.
Funder
National Health and Medical Research Council
Funding Amount
$234,250.00
Summary
Anxiety disorders [e.g., Post Traumatic Stress Disorder (PTSD)] are the most prevalent type of psychopathology in the industrialised world. They are associated with characteristic behavioural (e.g., heightened startle) and autonomic (e.g., cardiovascular) reactions. These disorders are often characterised as an inability to regulate the emotion of fear. Significant progress has been made in understanding the neural and cellular processes involved in the establishment of fear memories, but relati ....Anxiety disorders [e.g., Post Traumatic Stress Disorder (PTSD)] are the most prevalent type of psychopathology in the industrialised world. They are associated with characteristic behavioural (e.g., heightened startle) and autonomic (e.g., cardiovascular) reactions. These disorders are often characterised as an inability to regulate the emotion of fear. Significant progress has been made in understanding the neural and cellular processes involved in the establishment of fear memories, but relatively little is known about the mechanisms by which fear memories can be inhibited or suppressed. Understanding this latter process is a key to the development of effective treatments for anxiety disorders such as PTSD where the patient suffers from persistent, intrusive, unwanted trauma memories. A common experimental procedure for reducing learned fear is to repeatedly expose the subject to a fear-eliciting stimulus but without any aversive outcome. This procedure leads to a progressive loss, or extinction, of the fear reactions elicited by the stimulus. Historically, the extinction of fear was thought to be due to an erasure of the fear memory. However, recent evidence shows that extinction inhibits, rather than erases, the fear memory. Because the fear memories remain intact, some structure(s) in the brain must inhibit activity in the fear pathway. This project uses extinction of conditioned fear reactions in rat subjects to determine the structure(s) in the brain that inhibit fear memories and their behavioural and cardiovascular expression. It brings together the expertise of four well-established researchers and uses a combination of behavioural, physiological, immunohistochemical, tract tracing, and lesion approaches to achieve this aim. The proposed experiments will reveal the structure(s) in the brain that control the inhibition of fear, as well as the site(s) of this inhibition in the fear pathwayRead moreRead less
Role Of The Hypothalamus, Oxidative Stress And Angiotensin In Chronic Stress
Funder
National Health and Medical Research Council
Funding Amount
$535,333.00
Summary
Stress can trigger life threatening cardiovascular events and its impact is much greater when blood pressure is raised. We seek to determine which chemical type of brain neuron and which region is responsible for amplifying the responses to repeated stress in an animal model that closely resembles the human form of the disease. We will focus specifically on the hypothalamus which controls the sympathetic nervous system.
Aliskiren: Cardioprotection By Increased Bradykinin Levels?
Funder
National Health and Medical Research Council
Funding Amount
$295,236.00
Summary
Aliskiren is a new treatment for hypertension. Our recent studies indicate that aliskiren may have additional benefits for patients with ischaemic heart disease and heart failure. This research project will investigate the effects of aliskiren in different forms of heart disease in rats, in order to provide information that will help patients obtain the maximum benefit from this treatment.
Investigations Of Neural Pathways For Heat Loss And Heat Gain In Thermoregulation And Fever
Funder
National Health and Medical Research Council
Funding Amount
$349,486.00
Summary
This project aims to map the nerve pathways in the brain that participate in the regulation of body temperature in the laboratory rat. The area of the brain that will be studied is the hypothalamic region. We will determine how this region influences the constriction of blood vessels in the skin to reduce heat loss when an animal is exposed to a cool environment, or when it exhibits a fever in response to a bacterial infection. As well, we will compare the nervous pathway that controls the gener ....This project aims to map the nerve pathways in the brain that participate in the regulation of body temperature in the laboratory rat. The area of the brain that will be studied is the hypothalamic region. We will determine how this region influences the constriction of blood vessels in the skin to reduce heat loss when an animal is exposed to a cool environment, or when it exhibits a fever in response to a bacterial infection. As well, we will compare the nervous pathway that controls the generation of heat from fat tissue in response to cold or fever with those controlling blood flow to the skin. These nervous pathways may be critical for maintaining correct body temperature during general anaesthesia, infections or in the aged subjected to temperature extremes. Thus, they are of importance in the health and well-being of much of the population.Read moreRead less
Optimisation Of Salmonella Genotyping And Epidemiological Data Analysis For Detection And Investigation Of Outbreaks
Funder
National Health and Medical Research Council
Funding Amount
$508,051.00
Summary
Bacteria known as salmonella are the most important causes of food-borne diarrhoeal disease. They occasionally cause potentially fatal septicaemia, especially in young children and people with underlying disease. We estimate that more than 80,000 cases of salmonella infection occur in Australia, each year, at a cost to the community of $37 million. Salmonella are divided into more than 2000 different types, but one - called Typhimurium - causes about 40% of infections and a few others cause most ....Bacteria known as salmonella are the most important causes of food-borne diarrhoeal disease. They occasionally cause potentially fatal septicaemia, especially in young children and people with underlying disease. We estimate that more than 80,000 cases of salmonella infection occur in Australia, each year, at a cost to the community of $37 million. Salmonella are divided into more than 2000 different types, but one - called Typhimurium - causes about 40% of infections and a few others cause most of the rest. This means that is difficult to distinguish cases of salmonella infection that have originated from one source (an outbreak) from cases that have originated from another. Without this information, is it hard to track the source, which is usually inadequately cooked meat or chicken another food that has been contaminated with salmonella after preparation. There are several existing methods for fingerprinting salmonella, but they are quite slow or do not distinguish different strains well enough to identify outbreaks quickly. This means that sources of contaminated food are often not identified in time to prevent more cases occurring. We aim to develop a faster and more discriminatory system for fingerprinting salmonella, based on novel technology that can identify many small genetic sequences that occur in different combinations in different strains. As well, we will develop electronic scanning tools that will link the fingerprints of the salmonella strains with information about the people infected with them, such as the types of food and places where they have eaten, to identify patterns or clusters that indicate a common source. The more rapidly this can be done the sooner the source of contaminated food can be found and eliminated and additional cases can be prevented. This has important implications for public health - it will increase food safety and reduce illness and economic loss.Read moreRead less
Control Of Sympathetic Nerves That Talk To The Immune System
Funder
National Health and Medical Research Council
Funding Amount
$385,958.00
Summary
The two complex systems of the body, the immune system and the nervous system, communicate with each other. This proposal studies one of the major pathways from brain to immune system - sympathetic immuno-efferent nerves. In stroke, these pathways cause profound immunosuppression, causing susceptibility to infection. Their poorly understood central and peripheral pathways will be defined and mapped by this study.