Regulation Of Innate Immunity And Tumour Progression By Activating Transcription Factor 3
Funder
National Health and Medical Research Council
Funding Amount
$473,469.00
Summary
Toll-like receptors (TLRs) play an essential role in innate immune responses and are involved in initiating tumourigenesis via inflammatory pathways. We have shown that the transcription factor ATF3 is a negative regulator of TLR signalling. We will study how modulation of the activity of ATF3 affects the inflammatory response and tumour progression. This will provide a molecular basis on which to design therapeutic reagents for the treatment of cancer.
The Role Of NF-kB Transcription Factors In Regulating T Cell Transcription Networks
Funder
National Health and Medical Research Council
Funding Amount
$534,000.00
Summary
T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. T ....T cells are a key element of the adaptive immune response and help to distinguish between self and non-self. Hence, an inappropriate T cell response can lead to autoimmunity and chronic inflammatory disease. When T cells are activated by an immune signal they switch on the production of an array of proteins that control both T cell function and other arms of the immune system. The genes encoding these proteins possess molecular switches (promoters and enhancers) that respond to immune signals. These molecular switches bind groups of proteins known as transcription factors. One family of transcription factors that plays a key role in T cell function is the NF-kB family consisting of five different members, three of which are important in T cell function. Aberrant NF-kB function or expression has been associated with autoimmunity, chronic inflammation and cancer. In addition, NF-kB proteins are key components of transplant rejection. There is enormous interest in using the NF-kB pathway as a therapeutic target for these pathologies. We currently have a detailed knowledge of the biology of these factors through studies of mice lacking specific family members. While we know some of the genes that are switched on by the NF-kB proteins, we currently lack a sufficiently detailed knowledge of NF-kB-regulated genes in order to link the molecular function with the biological outcomes. In order to understand the molecular mechanism of NF-kB function and relate this to the biological outcomes, we need a global view of NF-kB action in the cell. This proposal uses both experimental and computational approaches to decipher the gene expression program controlled by NF-kB proteins in T cells. The T cell transcription networks in which NF-kB proteins participate will also be investigated. The knowledge generated by these experiments will provide a solid basis for designing therapeutic approaches based on the NF-kB pathway.Read moreRead less
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
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.