Inflammatory Pathways For Novel Therapeutic Interventions In Preterm Delivery
Funder
National Health and Medical Research Council
Funding Amount
$568,006.00
Summary
Preterm birth is common and carries severe risks for the child. Existing therapies are not very successful in arresting preterm labour or improving outcomes for the fetus. We have discovered that blocking inflammatory ‘sensor’ molecules can slow labour progression. This project will (1) increase our knowledge of the inflammatory pathways that initiate early labour, and (2) define the mechanism of action and safety of a new drug that has potential for delaying preterm birth in women.
Antagonist Of Corticotrophin Releasing Hormone As Therapeutic Agents For The Prevention Of Premature Birth In Humans
Funder
National Health and Medical Research Council
Funding Amount
$376,650.00
Summary
In developed countries the most common cause of the death of a newborn baby is premature delivery. Pre-term delivery remains the greatest cause of neonatal mortality in the western world and a major consumer of health dollars (approx. $5-7B per year in the US alone). However, a delay in the onset of labour from 20 to 25 weeks has been shown to result in a 55% greater probability of infant survival (550 fewer deaths per 1000). This project will allow: The development of new drugs that will allow ....In developed countries the most common cause of the death of a newborn baby is premature delivery. Pre-term delivery remains the greatest cause of neonatal mortality in the western world and a major consumer of health dollars (approx. $5-7B per year in the US alone). However, a delay in the onset of labour from 20 to 25 weeks has been shown to result in a 55% greater probability of infant survival (550 fewer deaths per 1000). This project will allow: The development of new drugs that will allow the extension of pregnancy term The development of protocols that will in turn reduce neonatal mortality. Additionally we believe that these new agents will be useful in preventing the onset of labour after fetal surgery. Currently there are no effective treatments capable of substantially changing delivery dates. Available therapeutics delay the onset of labour, at best, 24 hours. However, recent exciting results from our laboratories show that rising concentrations of the placental peptide Corticotrophin Releasing Hormone (CRH) are associated with the onset of labour. Further, we have also delayed the onset of labour in pregnant sheep by infusing a relatively insoluble CRH antagonist into the sheep fetus. Labour commenced ONLY AFTER the drug was withdrawn from the mother. This project builds upon an interdisciplinary team: medicinal chemists, molecular modellers, pharmacologists and endocrinologists, to further develop an exciting Australian discovery. Successful completeion of this research will, for the first time, allow the control of pregnancy duration MAXIMISING the benefits to mother and child, reducing mortality and later life morbidities typically associated with premature birth.Read moreRead less
This research investigates the factors regulating the transition of the lung from the fluid filled organ in fetal life to the air filled organ required at birth. Many preterm babies fail this transition and in order to survive, their lungs often require mechanical ventilation, which has been suggested to cause lung injury. Using synchrotron generated X-rays, we can determine how particular resuscitation techniques are able to reduce this injury and promote aeration at birth.
The Effects Of Pre-term Birth On The Baboon And Human Neonatal Kidney
Funder
National Health and Medical Research Council
Funding Amount
$349,248.00
Summary
LAY DESCRIPTION: Over the past two decades the incidence and survival after pre-term birth has increased substantially. Despite significant improvements in the treatment of these pre-term babies there remains a high incidence of kidney failure. The functional unit of the kidney is the nephron and they are formed in the kidney late in pregnancy at a time when many preterm babies are already delivered. Hence, it is important to determine what is the effect of preterm birth on the formation of neph ....LAY DESCRIPTION: Over the past two decades the incidence and survival after pre-term birth has increased substantially. Despite significant improvements in the treatment of these pre-term babies there remains a high incidence of kidney failure. The functional unit of the kidney is the nephron and they are formed in the kidney late in pregnancy at a time when many preterm babies are already delivered. Hence, it is important to determine what is the effect of preterm birth on the formation of nephrons. We have shown that the baboon is an excellent model of kidney development in humans. Like humans, we can prematurely deliver baboons and maintain them in a neonatal intensive care unit after birth. In this model, we have evidence to suggest that the formation of the the nephrons within the kidneys of the pre-term infants is impaired and we predict that this leads to impaired kidney function after birth and to susceptibility for renal disease in adulthood. In this study, we will examine kidney function in preterm baboon and human babies and also undertake studies in autopsied kidneys from baboon and human pre-term infants. We will determine whether the number and the cellular structure of the nephrons is affected by preterm delivery and if so, whether kidney function is affected. By comprehensively examining the medical records of the mother and babies, we also aim to identify factors in the care of the mother prior to birth, or of the baby after birth which may link to impaired nephron formation and kidney dysfunction in the baby. We will also determine whether administration of retinoic acid to the baboon preterm baby soon after birth can stimulate the formation of nephrons. The findings of this study will provide important new insights into the mechanisms of kidne failure in preterm babies and will identify potential strategies to prevent nephron loss and enhance nephron formation in preterm infants, which will in turn have long-term implications to kidney health.Read moreRead less
The RgpA-Kgp Proteinase-adhesin Complex And Virulence Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$527,310.00
Summary
Periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth which can result in tooth loss. The disease is a major public health problem with a large economic burden. A bacterium Porphyromonas gingivalis has now been identified as a major causative agent of chronic periodontitis. We have identified a major virulence factor of P. gingivalis. This virulence factor is a complex of proteins, encoded by two genes, and is involved in binding and destruction of h ....Periodontitis is a bacterial-associated inflammatory disease of the supporting tissues of the teeth which can result in tooth loss. The disease is a major public health problem with a large economic burden. A bacterium Porphyromonas gingivalis has now been identified as a major causative agent of chronic periodontitis. We have identified a major virulence factor of P. gingivalis. This virulence factor is a complex of proteins, encoded by two genes, and is involved in binding and destruction of host tissue. When used as a vaccine in animal models the protein complex protects against P. gingivalis infection. Animal protective sera recognises a segment of the protein complex involved in binding to host substrates. The aim of this project is to continue this work on the characterisation of this complex and its role in virulence in an approach to ultimately develop a defined vaccine against P. gingivalis based on this protein complex, in particular the sequences involved in binding. The expected outcome of this research is the further biochemical characterisation of the RgpA-Kgp protein complex and its role in virulence as well as development of a defined vaccine prepared using recombinant DNA and chemical synthesis techniques that protects against P. gingivalis infection in animal models of disease.Read moreRead less
Polymicrobial Pathogenesis In A Murine Periodontitis Model.
Funder
National Health and Medical Research Council
Funding Amount
$235,500.00
Summary
Severe periodontal disease is a chronic inflammatory disease of the tooth's supporting tissues and is associated with specific pathogenic bacteria. The disease has a large economic burden and is a major public health problem. Three bacterial species have recently been shown to be closely associated with advanced periodontal disease in humans. One of these three bacterial species has been shown to produce periodontal disease in a mouse model of disease and the major proteins on the cell surface o ....Severe periodontal disease is a chronic inflammatory disease of the tooth's supporting tissues and is associated with specific pathogenic bacteria. The disease has a large economic burden and is a major public health problem. Three bacterial species have recently been shown to be closely associated with advanced periodontal disease in humans. One of these three bacterial species has been shown to produce periodontal disease in a mouse model of disease and the major proteins on the cell surface of this bacterium have been characterized. Further, in this mouse model it has been demonstrated that killed cells of the bacterium or the major surface proteins when used as a vaccine prevent development of disease. The purpose of the current proposal is to extend this work to include all three bacterial species that have been associated with disease in humans. The major surface proteins of all these bacterial species when grown together as high density polymicrobial complexes will be determined. Recent results have shown that in high-density, polymicrobial cultures bacteria communicate using signalling systems which can alter the expression of cell surface proteins associated with disease. The ability of the three bacterial species, when grown in polymicrobial culture, to cause periodontal disease in the mouse model will be determined. This will allow the determination of whether a single species and-or multispecies vaccine is capable of protecting against disease in this model. The significance of the work is that it will increase our understanding of the bacteria associated with periodontal disease and it may lead to the development of an effective vaccine to help prevent disease in humans.Read moreRead less
Iron/hemin Transport Systems Of Porphyromonas Gingivalis
Funder
National Health and Medical Research Council
Funding Amount
$392,036.00
Summary
Periodontitis is a bacterial-associated disease of the supporting structures of the teeth and can result in tooth loss. The disease is classified as a major public health problem with an enormous economic burden. A bacterium, Porphyromonas gingivalis, has now been implicated as a major causative agent of periodontitis in adults. To survive and grow within humans pathogenic bacteria must be able to acquire essential elements, including iron. The human host has developed a variety of mechanisms to ....Periodontitis is a bacterial-associated disease of the supporting structures of the teeth and can result in tooth loss. The disease is classified as a major public health problem with an enormous economic burden. A bacterium, Porphyromonas gingivalis, has now been implicated as a major causative agent of periodontitis in adults. To survive and grow within humans pathogenic bacteria must be able to acquire essential elements, including iron. The human host has developed a variety of mechanisms to restrict the amount of iron available as a means of limiting the growth of bacterial pathogens. In response to this iron limitation Porphyromonas gingivalis has developed novel ways of obtaining this essential element. We have identified a novel iron transport system that P. gingivalis uses to obtain iron from the human host. A component of this transport system, FetB is a surface protein antigen. The aims of this project are to: i. Determine the mechanism by which this novel iron transport system functions by genetic manipulation of the organism using molecular biology techniques. ii. Determine how important this transport system is for the pathogenicity of the bacterium. iii. Prepare the FetB protein using recombinant DNA technology. iv. Test the recombinant FetB protein and another iron transport protein (Tlr) in animal models to determine their efficacy as a vaccine for periodontitis. The expected outcomes of this research are:- i. the understanding of how P. gingivalis transports iron. ii. an understanding of the importance of iron transport systems to the pathogenicity of the bacterium. iii. a P. gingivalis vaccine with efficacy in animals based on an iron transport protein(s).Read moreRead less
Towards Reducing The Susceptibility Of “high Risk” Infants To Allergic Asthma By Therapeutic Modulation Of Immunoregulatory Functions In The Pregnant Mother.
Funder
National Health and Medical Research Council
Funding Amount
$445,681.00
Summary
This project will deliver information in relation to the potential use and underlying modes of action of a therapeutic agent fed to pregnant mothers at high risk for atopic children, to protect against allergic asthma development in their offspring. Furthermore, the project will address the benefits of this therapeutic agent in relation to protection against inflammation induced preterm birth.