Understanding The Pathogenesis And Heterogeneity Of Autoimmunity As Failure Of Multiple Steps
Funder
National Health and Medical Research Council
Funding Amount
$504,023.00
Summary
Autoimmune diseases like diabetes, thyroid disease or rheumatoid arthritis affect around 1 in 15 people in Australia. It is clear that defects in a number of different genetic mechanisms can contribute to the development of autoimmunity. But it is currently not clear how these different mechanisms need to interact to prevent the onset of disease. This grant seeks to understand these interactions and how defects in two or more tolerance mechanisms can lead to autoimmunity.
Molecular Genetic Analysis Of BRCT Domain Function And RhoGEF Signalling In DNA-damage Response And Apoptosis.
Funder
National Health and Medical Research Council
Funding Amount
$195,691.00
Summary
Cancers arise as a consequence of a series of genetic changes, usually by mutation of DNA. DNA is consistently exposed to an array of damaging agents, but the majority of mutations are corrected by cellular repair mechanisms. We now know that if these mechanisms work normally, too few mutations persist for cancer to result. However if these DNA damage repair mechanisms are themselves faulty, a high mutation rate occurs and a high risk of cancer results. DNA damage has another outcome. If the dam ....Cancers arise as a consequence of a series of genetic changes, usually by mutation of DNA. DNA is consistently exposed to an array of damaging agents, but the majority of mutations are corrected by cellular repair mechanisms. We now know that if these mechanisms work normally, too few mutations persist for cancer to result. However if these DNA damage repair mechanisms are themselves faulty, a high mutation rate occurs and a high risk of cancer results. DNA damage has another outcome. If the damage is too extensive, the cell commits suicide, not because it cannot function, but because it senses the DNA damage and chooses to die. One poorly understood aspect of the response to DNA damage is how the cell senses the damage and activates the suicide process. We have discovered a novel gene that appears to play a role in this sensing and suicide signalling process. The mouse version of this gene can itself act as a cancer-causing gene. We propose, however, to study the equivalent gene in Drosophila melanogaster, a more powerful experimental system, to characterise in detail its role in these processes. In this way we hope to generate a much more detailed understanding of the way that cells deal with DNA damage and choose suicide when the damage is too severe.Read moreRead less
Infrared Thermal Imaging: An Innovative Technique To Assess Peripheral Body Temperature.
Funder
National Health and Medical Research Council
Funding Amount
$192,710.00
Summary
Insomnia is a significant health issue, with 10-12% of the general population reporting sleeping difficulties requiring treatment. Pharmacological treatment with hypnotics-sedatives remain the main treatment strategy for most insomnias, despite the adverse side-effects. A better understanding of the physiological triggers for sleep will make it possible to develop more specific treatments for insomnia. Sleep onset is reported to be associated with changes in body temperature. Broadly speaking, s ....Insomnia is a significant health issue, with 10-12% of the general population reporting sleeping difficulties requiring treatment. Pharmacological treatment with hypnotics-sedatives remain the main treatment strategy for most insomnias, despite the adverse side-effects. A better understanding of the physiological triggers for sleep will make it possible to develop more specific treatments for insomnia. Sleep onset is reported to be associated with changes in body temperature. Broadly speaking, sleep onset has been linked with a rapid reduction in core temperature through increased peripheral heat loss. It has been suggested from this that sleep onset insomnia may result from the failure to efficiently lose heat at the periphery and thus, reduce core temperature. To date, the analysis of peripheral temperature physiology has been limited to single temperature thermistors attached to discrete body areas. This technique typically provides very limited information about the dynamic temperature changes. Recently, low cost, high resolution thermal imaging systems have become available, enabling the measurement of real-time changes in peripheral temperature across the whole body simultaneously. This development will help to significantly improve our understanding of the physiological mechanisms involved in both sleep onset and insomnia. The aim of this project then, is to determine whether an impaired capacity to lose heat at the periphery contributes to sleep onset insomnia in both young and older adults. The results of this project will provide insight into whether a reduced capacity to dissipate heat results in an extended sleep onset latency, greatly enhancing our knowledge of the physiology of sleep onset and sleep onset insomnia. In turn, treatments may be developed that directly manipulate the physiological triggers for sleep, minimising the dependence on sedative-hypnotics and the associated adverse effects of these agents.Read moreRead less
Identifying The Underlying Mechanisms Responsible For The Generation Of Pathogenic B Cells In Type 1 Diabetes
Funder
National Health and Medical Research Council
Funding Amount
$163,755.00
Summary
Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are r ....Type 1 diabetes (T1D) occurs when the body's own immune system mistakenly attacks and destroys all the beta cells of the pancreas which produce insulin, a hormone essential for regulating sugar levels in the blood. The non-obese diabetic (NOD) mouse develops a form of T1D closely resembling the human disease, and as a model, has led to numerous important insights into its cause. Based on studies in NOD mice, it is now well accepted that a class of cell in the immune system, termed T cells, are responsible for most of the damage to the beta cells in T1D. Recent work in this model, however, has demonstrated that another class of immune cell, termed B cells, also play an important role in T1D as NOD mice made deficient in these cells no longer develop disease. In addition to producing antibodies, B cells are one of the few cell types which are able to take up and present protein fragments in a form recognizable to T cells. Normally, this only leads to the activation of T cells recognising foreign insults, like viruses or bacteria, resulting in their destruction. We have shown that a dangerous population of B cells can arise in NOD mice that can specifically take up beta cell proteins and present them to the T cells, which subsequently become armed to recognise and destroy the beta cells. Just like T cells, B cells that recognize the body's own proteins are normally eliminated in healthy mice and human individuals. This research proposal aims to determine the faulty immune mechanisms that give rise to the beta cell specific B cells in NOD mice. We have also set out to identify the diabetes susceptibility genes which control the generation of this dangerous population of B cells in this model. By understanding how these dangerous B cells are generated in NOD mice, we hope to form the basis for new therapies aimed at inhibiting these cells from forming in T1D susceptible humans, thus preventing the disease at an early stage.Read moreRead less
Identification And Analysis Of Novel Replication Initiation Factors In Staphylococcus Aureus
Funder
National Health and Medical Research Council
Funding Amount
$311,789.00
Summary
Multi-drug resistant Golden staph is a serious medical problem around the world because strains are often resistant to commonly used treatments; new drugs are therefore urgently required. DNA replication is a fundamental process that is essential for the survival of all cellular organisms. This project aims to identify and characterise novel factors involved in DNA replication in Golden staph, which represent potential drug targets.
Plasmids are extra mini-chromosomes that are present in many bacteria. They carry information that enables their hosts to survive and prosper in hostile environments. Plasmids are able to spread rapidly between bacteria, ensuring that the information they carry is rapidly disseminated throughout bacterial populations. Many plasmids carry information that increases the virulence of their host bacteria, because it adds to their repertoire of toxins and other adjuncts to invasiveness and colonisati ....Plasmids are extra mini-chromosomes that are present in many bacteria. They carry information that enables their hosts to survive and prosper in hostile environments. Plasmids are able to spread rapidly between bacteria, ensuring that the information they carry is rapidly disseminated throughout bacterial populations. Many plasmids carry information that increases the virulence of their host bacteria, because it adds to their repertoire of toxins and other adjuncts to invasiveness and colonisation, or enables them to survive in the presence of antibiotics. The emergence of multi-drug resistant bacteria and the rapid spread of the ability of bacteria to withstand most antibiotics available to date were mediated by plasmids. Plasmids also carry information that ensures their own survival. The consequence of this is that their bacterial hosts retain the plasmids, even when it is no longer beneficial to do so. For example, plasmids carrying information for resistance to antibiotics are not lost when their bacterial hosts grow in the absence of antibiotics. This is because plasmids have control systems, which ensure that on the one hand, replication of the plasmid keeps pace with the replication of its host, and on the other hand that the plasmid does not produce so many copies of itself that it overwhelms its host. This project examines the intricate regulatory system that a group of antibiotic-resistance plasmids uses to ensure that on average each plasmid molecule is replicated once per bacterial cell cycle. This system uses an antisense RNA, a tertiary RNA structure (pseudoknot) that acts as a translational switch, and a protein that interacts with different sequences on the plasmid to initiate replication. Detailed knowledge of the processes underlying this complex system is required if we are to develop new treatments that will lead to elimination of antibiotic-resistance and virulence-contributing plasmids from populations of pathogenic bacteria.Read moreRead less
The Role Of MHC Class I Expression On Pancreatic Ductal Lineage Cells In The Pathogenesis Of Type I Diabetes (TID).
Funder
National Health and Medical Research Council
Funding Amount
$484,300.00
Summary
MHC molecules act as traffic lights to the immune system telling it whether to stop or go, so that only when there is an infection does the immune system receive the signal to destroy target cells. However, the immune system in Type 1 Diabetes patients receives signals to destroy the insulin-producing cells when there is no apparent infection. We aim to determine where the faulty traffic signal occurs and so be in a better position to design intervention strategies to prevent Type 1 Diabetes.
Factors Regulating Initiation, Progression And Submucosal Invasion In Gastric Cancer.
Funder
National Health and Medical Research Council
Funding Amount
$450,750.00
Summary
Gastric cancer is the second most common cause of death in humans. It is strongly associated with Helicobacter pylori, a common and easily transmitted bacterium which infects about half the world's population. Exactly how Helicobacter pylori (HP) causes cancer, and why it does so in only a small percentage of those infected is unknown. It is clear however that Helicobacter species that produce a strong inflammatory response in the host and possess a full complement of pathogenic (disease-associa ....Gastric cancer is the second most common cause of death in humans. It is strongly associated with Helicobacter pylori, a common and easily transmitted bacterium which infects about half the world's population. Exactly how Helicobacter pylori (HP) causes cancer, and why it does so in only a small percentage of those infected is unknown. It is clear however that Helicobacter species that produce a strong inflammatory response in the host and possess a full complement of pathogenic (disease-associated) genes are more strongly associated with cancer development after long-term infection than others. We have recently developed a genetically modified mouse which has a minor defect in a regulatory pathway which controls some aspects of gut inflammation. Surprisingly 100% of these mice rapidly develop gastric cancer which has many similarities with the human disease, including inflammation, loss of structure of the stomach lining and penetration of cancerous cells into the muscle layers below. The objectives of this project are to work out whether HP induces similar changes in normal stomach cells as occurs in our defined mouse model of gastric cancer. Specifically we will determine if HP disturbs the way a particular mediator of inflammation works, and if so the way this impacts on certain stomach genes which detect cancerous cells and prevent tumor growth.Read moreRead less