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 Labour commenced ONLY AFTER the drug was withdrawn from the mother.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
Regulatory RNAs Underlying Genetic Associations With Ankylosing Spondylitis
Funder
National Health and Medical Research Council
Funding Amount
$431,201.00
Summary
Ankylosing spondylitis is a chronic inflammatory disease affecting the spine and causing back pain. The diagnosis of the disease is delayed by up to 10 years due to lack of accurate tests. We aim to identify molecular signatures of the disease that might be used to distinguish inflammatory processes typical of the disease and other causes of back pain. This would allow earlier and more accurate diagnosis of the disease and result earlier patient treatment and better health outcomes.
Nuclear Import Of The HIV-1 Pre-integration Complex: Mechanism And Therapeutic Implications
Funder
National Health and Medical Research Council
Funding Amount
$425,250.00
Summary
The human immunodeficiency virus (HIV) has a unique feature distinguishing it from other retroviruses the ability to replicate in non-dividing cells such as in macrophage-microglia cells which are among the prime target cells for virus infection. The viral genome needs to be integrated into the host cell chromosome in order to infect cells productively. The host cell s genome is not normally accessible because it is located inside the nucleus, separated from the rest of the cell by the barrier o ....The human immunodeficiency virus (HIV) has a unique feature distinguishing it from other retroviruses the ability to replicate in non-dividing cells such as in macrophage-microglia cells which are among the prime target cells for virus infection. The viral genome needs to be integrated into the host cell chromosome in order to infect cells productively. The host cell s genome is not normally accessible because it is located inside the nucleus, separated from the rest of the cell by the barrier of the nuclear envelope (NE). However, HIV has found a way to transport its genome to the nucleus in a complex together with other viral-cellular proteins, the pre-integration complex (PIC), through the intact NE of non-dividing cells. This is a crucial step of viral infection and if blocked could prevent the establishment and spread of HIV infection. Thus far it is unclear how the large HIV PIC accesses the nucleus and which viral and cellular proteins are essential for the navigation of the PIC through the NE and into the nucleus. Using fluorescent labels on the key components of the HIV PIC including the DNA in combination with confocal laser scanning microscopy and a novel optical single-transporter recording technique, we will be able to visualize the PIC on its way through the NE for the first time. Mutational analyses will further identify the key residues of viral proteins and the cellular nuclear transport machinery utilized during the transport. The results of this study will literally provide a clear picture of nuclear import of the HIV PIC. The future aim of elucidating this essential step in HIV replication is to identify new targets for anti-retroviral drug interventions that may be less prone to side effects and development of resistance than the currently available drug regimens.Read moreRead less
The Leucine Rich Repeat Kinase 1 And 2 Genes Are Modulators Of Alternative Splicing - Implication For Neurodegeneration
Funder
National Health and Medical Research Council
Funding Amount
$583,809.00
Summary
Alzheimer's disease (AD) and Parkinson's disease (PD) are the two common causes of dementia and neurodegeneration. Through positional cloning, we have identified the leucine rich repeat kinase (LRRK1) 1 gene as a modulator of alternative splicing. We have subsequently shown that its homologue, LRRK2 has a similar biological activity. We propose to study the the genetic and biochemical role of LRRK1 and LRRK2 in neurodegeneration in terms of its effect in splicing.
Cloning Of Human NK Cells And Macrophages Carbohydrate Receptors
Funder
National Health and Medical Research Council
Funding Amount
$489,750.00
Summary
Lymphocytes, also known as white blood cells, are important for the well being of all individuals as these are the cells which fight infection by microorganisms. The lymphocyte gets its information about enviroment and communicates with other cells using molecules on the cell surface. We are examining a group of molecules found on the surface of different lymphocytes which bind different sugars, and also to characterised new cell surface molecules that interact with carbohydrates. These studies ....Lymphocytes, also known as white blood cells, are important for the well being of all individuals as these are the cells which fight infection by microorganisms. The lymphocyte gets its information about enviroment and communicates with other cells using molecules on the cell surface. We are examining a group of molecules found on the surface of different lymphocytes which bind different sugars, and also to characterised new cell surface molecules that interact with carbohydrates. These studies will examine the structure of the the molecules that interact with with sugars, in order to understand how these give messages to the lymphocyte to trigger various functions that these cell perform in the immune response. We will isolate the genes for these and study their function in greater detail. The cell surface carbohydrate receptors represents several different families of molecules, it is highly likely that these have important roles in the immune response. The potential significance of studying these lymphocyte cell surface molecules is in defining the functional properties of these molecules, the results of which will give us novel insights into the molecular mechanisms involved in the generation of immune responses, the mechanism of immuno deficiency and autoimmunity.Read moreRead less
Molecular Characterisation Of Lipid Droplet Function
Funder
National Health and Medical Research Council
Funding Amount
$496,446.00
Summary
Fat is stored inside cells in spherical structures called lipid droplets. The accumulation of fat within lipid droplets underlies obesity. This project aims to understand how fat is stored within lipid droplets and how it is released when energy is required. In particular, we will look at two types of protein which move to lipid droplets under certain energy conditions and attempt to unravel how these proteins control fat storage and release. The first protein we will study, caveolin, normally a ....Fat is stored inside cells in spherical structures called lipid droplets. The accumulation of fat within lipid droplets underlies obesity. This project aims to understand how fat is stored within lipid droplets and how it is released when energy is required. In particular, we will look at two types of protein which move to lipid droplets under certain energy conditions and attempt to unravel how these proteins control fat storage and release. The first protein we will study, caveolin, normally associates with regions of the cell surface but moves to lipid droplets when cells are fed lipids. Mice which lack this protein eat more food but remain leaner than normal mice. Understanding how caveolin moves to lipid droplets and how it controls fat accumulation will therefore provide new insights into obesity and conditions associated with obesity, such as diabetes. The second protein to be studied, Rab18, is a member of a protein family which controls membrane movement within cells. Rab18 moves to lipid droplets when lipid release is stimulated. Therefore studies of Rab18 can provide new insights into the way lipids are released from fat tissue under conditions of starvation. The project will provide fundamental new insights into the basic mechanisms by which we store energy and the energy imbalances which cause obesity and related diseases.Read moreRead less
The Design And Synthesis Of Sialyltransferase Inhibitors As Anti-metastatic Agents
Funder
National Health and Medical Research Council
Funding Amount
$273,629.00
Summary
The prevalence of cancer and, in particular, cancer that spreads throughout the body has risen over the past twenty years in the human population and causes significant human mortality. A correlation between some of a cancerous cell's surface componentary and the ability of this cell to spread throughout the body has been established. This research project will provide a range of chemical entities (probes) that will intervene in this spreading process (metastasis). These probes will be the basis ....The prevalence of cancer and, in particular, cancer that spreads throughout the body has risen over the past twenty years in the human population and causes significant human mortality. A correlation between some of a cancerous cell's surface componentary and the ability of this cell to spread throughout the body has been established. This research project will provide a range of chemical entities (probes) that will intervene in this spreading process (metastasis). These probes will be the basis for a drug discovery programme that targets a particular aspect of the spreading process. Through molecular modelling, drug candidate synthesis and evaluation of these compounds in relevant test tube (in vitro) assays it is envisaged that a number of candidate compounds will then be evaluated in an animal model (in vivo assay). The technology to be used in this project is comparable to that which we used in the discovery of the recently approved influenza drug, Relenza?.Read moreRead less
Biological Characterisation Of The Opiod Receptor Sigma 1 Gene In The Frontotemporal Dementia And Motor Neuron Disease
Funder
National Health and Medical Research Council
Funding Amount
$480,211.00
Summary
Frontotemporal dementia (FTD) and motor neuron disease (MND) are the two common causes of dementia and neurodegeneration. We have identified a new genes that causes familial FTD and MND in pedigrees affected with dementia and-or MND.This project will study the expression and function of this new FTD-MND gene to determine its role in the aetiology and pathology of this complex of neurodegenerative disorders.