Mechanisms For Ageing Changes In The Hepatic Sinusoid
Funder
National Health and Medical Research Council
Funding Amount
$413,750.00
Summary
We recently discovered changes in the blood vessels of the liver that occur with old age that we have called pseudocapillarisation. These changes include thickening of the liver sinusoidal endothelium, deposition of basal lamina and collagen, and marked loss of specialized pores within the endothelium called fenestrations. These changes have profound effects on the transfer of many substrates including toxins, drugs, oxygen, hormones and lipids from the blood into the liver and thus may explain ....We recently discovered changes in the blood vessels of the liver that occur with old age that we have called pseudocapillarisation. These changes include thickening of the liver sinusoidal endothelium, deposition of basal lamina and collagen, and marked loss of specialized pores within the endothelium called fenestrations. These changes have profound effects on the transfer of many substrates including toxins, drugs, oxygen, hormones and lipids from the blood into the liver and thus may explain in part the fact that old age is the major risk factor for many diseases and adverse drug reactions. To further understand the mechanisms for these important ageing liver changes, we are proposing several studies. First, the effects of caloric restriction on the liver blood vessels will be studied because caloric restriction delays the primary ageing process. Second we will study the effects of ageing on F-actin, ATP, caveolin-1 and VEGF because these mechanisms have established roles in regulating the structure and function of the liver blood vessels and in particular their fenestrations. Finally we will determine whether VEGF can reverse the ageing changes in the liver blood vessels and stimulate the formation of new fenestrations within these blood vessels. Our research provides one mechanism for the inexorable association between old age and susceptibility to disease - based on primary ageing changes in the liver. As well as increasing our understanding of the cellular changes for ageing and the basic mechanisms involved in the regulation of the liver endothelial cells and their fenestrations, this proposed research will provide a foundation for the development of therapeutic interventions for the prevention and treatment of some age-related disorders.Read moreRead less
The Structural Basis Of Direction Selectivity In The Retina
Funder
National Health and Medical Research Council
Funding Amount
$401,705.00
Summary
The retina is part of the central nervous system and there are almost one hundred types of retinal neurons which process visual information before it is passed up the optic nerve to the brain. This project examines how some of these neurons are wired together to form a simple neuronal circuit that detects the direction of a moving object. The elucidation of the cellular mechanisms of direction selectivity will provide an important paradigm of complex processing by simple neuronal circuits, with ....The retina is part of the central nervous system and there are almost one hundred types of retinal neurons which process visual information before it is passed up the optic nerve to the brain. This project examines how some of these neurons are wired together to form a simple neuronal circuit that detects the direction of a moving object. The elucidation of the cellular mechanisms of direction selectivity will provide an important paradigm of complex processing by simple neuronal circuits, with direct relevance to information processing in other parts of the central nervous system. In particular, the project may provide strong evidence for two neuronal strategies that may be of general significance. First, information may be processed at a very local level, which would greatly increase the computational power of a single neuron. Second, neurons may make selective contact with only some processes of an input neuron, which would require novel mechanisms for producing the necessary specificity.Read moreRead less
Spatial Arrangement And Three-dimensional Structure Of Human Centromeres
Funder
National Health and Medical Research Council
Funding Amount
$283,000.00
Summary
Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tight ....Centromeres occur at the main constriction of chromosomes. They allow duplicated chromosomes to divide, control cell division and are involved in the control of gene expression. Faulty centromeres are found in many types of cancer and in other genetic diseases. They are also implicated in extra-chromosome disorders such as Down syndrome. Centromeres have a different structure to the rest of the chromosome and it is this structure we wish to study. We want to see how centromere DNA folds up tightly at the centromere. We also want to find out why centromeres locate in certain regions of the nucleus, because this may influence how the centromere works and how they regulate genes. Human centromeres come in many sizes and forms; by looking at a wide range of human centromeres, common structural and spatial properties will emerge. We have discovered very small centromeres - neocentromeres - which are much easier to study than other centromeres. We have used these centromeres to construct human minichromosomes, which we believe represent the main, all-human way forward to treat people with gene therapy. One way to help us achieve our aims is to stretch out centromeres in a controlled way to make it easier to visualise their structure. Our tools will be antibodies, fluorescently-labelled proteins and high resolution microscopes. These include an electron microscope, and microscopes that can produce optical sections and in turn a 3D image. One of these is the confocal laser scanning microscope; the other involves removal of out-of-focus light from images using deconvolution software to achieve the same goal. We will detect different centromere proteins with different fluorochromes for fluorescence microscopes and different sizes of gold particles for the electron microscope. Using these microscopes we have already been able to find out where one of our neocentromeres is located within the nucleus. We have also started to look at centromeres with the electron microscope.Read moreRead less
Development Of Bacterial Mechanosensitive Channels As Nanodevices In Liposome Systems For Targeted Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$502,341.00
Summary
Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and a ....Liposomes are among the most advanced mainstream particulate drug carriers in modern medicine. They vary in complexity, but in their most basic form consist of naturally occurring phospholipid vesicles, capable of encapsulating a wide range of drugs. Such liposomes provide a high degree of biocompatibility and a physical barrier that protects the drug cargo from degradative enzymes in the patient. Furthermore, liposomes provide an effective, non-toxic method to solubilise hydrophobic drugs and administer potent and even highly toxic drugs such as the anthracyclines, Doxorubicin and Daunorubicin (clinically approved anti-cancer treatments), Amphotericin B (fungal disease therapy) and Taxol (cancer therapy).The focus of this project is to incorporate nanovalves into these drug delivery systems, in the form of bacterial mechanosensitive (MS) channels, to facilitate the controlled and rapid release of encapsulated drugs at targeted tumours or disease tissues. The successful completion of this project represents a significant advance on existing liposomal drug delivery systems because MS channels open and release the drug into or onto the target cell immediately following liposome binding. Liposomal drug delivery systems offer the additional advantages that they concentrate the drug inside the target tissue, thereby increasing its efficacy; reduce the exposure of healthy cells to toxic drugs; and increase safety to patients through loading site-specific drugs into site-directed liposomes. Specifically this project will develop: 1. Liposome formulations in which the MS channels are closed, but poised to open upon binding to the target cell. 2. Customised MS channels designed to optimize controlled release. 3. Structural information that will assist in the treatment of channelopathies linked to MS channels, i.e. diseases resulting from defects in MS ion channel function (e.g. muscular dystrophy, cardiac arrhythmias, autosomal-dominant polycystic kidney disease).Read moreRead less
Distribution Of Neurotransmitter Receptors On Identified Cell Populations In The Primate Retina
Funder
National Health and Medical Research Council
Funding Amount
$421,812.00
Summary
Neurons (nerve cells) communicate with each other by releasing chemicals called neurotransmitters at specialized sites called synapses. Each neuron has synaptic receptors, which determine how it will respond to neurotransmitters released by other neurons. The molecular structure and function of these receptors is well understood. Much less is known about the rules that govern which receptor types are expressed by each type of neuron, and how these receptors are distributed to the appropriate syn ....Neurons (nerve cells) communicate with each other by releasing chemicals called neurotransmitters at specialized sites called synapses. Each neuron has synaptic receptors, which determine how it will respond to neurotransmitters released by other neurons. The molecular structure and function of these receptors is well understood. Much less is known about the rules that govern which receptor types are expressed by each type of neuron, and how these receptors are distributed to the appropriate synapses so as to allow the normal function of the nervous system. We will study the distribution of neurotransmitter receptors on identified neurons in the retina. The retina is part of the central nervous system and its highly ordered structure makes it an ideal model nervous system. We will compare the distribution of receptors on neurons that play distinct functional roles in colour and movement detection. These experiments will advance our understanding of the normal functioning of the nervous system.Read moreRead less
Dissecting The Molecular Basis Of The Malaria Parasite-Erythrocyte Tight Junction Complex
Funder
National Health and Medical Research Council
Funding Amount
$547,356.00
Summary
The parasites that cause malaria disease must invade the human red blood cell to complete their lifecycle. Invasion requires the formation of a complex interface between parasite and red cell called the Tight Junction. However, this structure's molecular makeup is entirely unknown. Our research will use a combination of state-of-the-art microscopy and genetics to define, for the first time, the junction's organization, providing a critical platform for the development of a malaria vaccine.
Mechanosensitive Channels: Antimicrobials, Channelopathies And Nanovalves For Drug Delivery
Funder
National Health and Medical Research Council
Funding Amount
$673,953.00
Summary
Liposomal drug delivery systems (LDDS) are one of the most advanced particulate drug carriers in modern medicine. The ultimate goal of this project is to optimize a nanotechnology approach for improved control of therapeutic drug delivery for chemotherapy. The approach is using bacterial mechanosensitive channel MscL designed to act as a molecular nanovalve for localised drug release.