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
Synaptic Environment Of Nociceptive Inputs To The Spinal Cord
Funder
National Health and Medical Research Council
Funding Amount
$499,860.00
Summary
Pain affects everyone at some stage in their life. Usually, the pain subsides by itself as the underlying cause is resolved. Thus, the damaged tissue heals or we move away from a potentially injurious stimulus and we become free of pain. However, pain can persist for two main reasons: the underlying cause cannot be treated adequately and the painful stimulus continues; or the pain is maintained long after the primary stimulus has resolved. This ongoing pain often is resistant to alleviation by c ....Pain affects everyone at some stage in their life. Usually, the pain subsides by itself as the underlying cause is resolved. Thus, the damaged tissue heals or we move away from a potentially injurious stimulus and we become free of pain. However, pain can persist for two main reasons: the underlying cause cannot be treated adequately and the painful stimulus continues; or the pain is maintained long after the primary stimulus has resolved. This ongoing pain often is resistant to alleviation by common analgesics. Therefore, a major aim of the pharmaceutical industry is the development of new drugs to target persistent pain. This requires a thorough understanding of how the nerves that detect painful stimuli transmit that information into the spinal cord, and then on to the brain, where we construct a conscious perception of the pain. Various kinds of painful stimuli, such as tissue damage, noxious chemicals, or extreme temperatures, are detected by different types of nerves. Each nerve type can be identified by its characteristic chemical profile. Recently, we found that some of these nerves probably do not transmit their messages to the spinal cord in the way everyone had thought. This means that there must be an alternative way for many types of painful stimuli to be transmitted into the spinal cord. In this project, we will use a sophisticated suite of modern microscopic and electrical recording techniques to find out what this alternative mechanism is. Our central idea is that most types of painful stimuli simultaneously activate two types of sensory nerves. These nerves then connect with specific nerve cells in the spinal cord before painful information is relayed to the brain. Our proposal suggests a new mechanism for understanding how pain can develop from being an acute defensive reaction to a chronic problem. In turn, this should lead to improved strategies for developing and testing new analgesic drugs.Read moreRead less
A Novel Patch-fluorimetry Technique For Investigating Structural Changes During Gating Of Mechanosensitive Ion Channnels
Funder
National Health and Medical Research Council
Funding Amount
$387,018.00
Summary
Membrane proteins, especially membrane channels play an important role in regulating the flow of substances across the cell. Dysfunction in these channels can lead to a variety of diseases. Thus approximately 60% of drug development is targeted against such proteins. In our research, we are looking at membrane channels found in bacteria. Understanding the function of these channels will help us develop novel anti-bacterial agents. It will also aid to understand a role of ion channels in disease.
Use Of Novel Transfection Protocols To Study Protein Trafficking In Malaria-infected Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$211,527.00
Summary
Malaria kills between 1 and 3 million children each year. In addition, the disease debilitates the adult population in malaria-endemic areas, thereby contributing to the cycle of poverty in many third world countries. As resistance to existing antimalarial drugs increases, there is an urgent need to understand the workings of the parasite at a molecular level to enable the development of alternative antimalarial strategies. During part of its life cycle, the malaria parasite infects the erythroc ....Malaria kills between 1 and 3 million children each year. In addition, the disease debilitates the adult population in malaria-endemic areas, thereby contributing to the cycle of poverty in many third world countries. As resistance to existing antimalarial drugs increases, there is an urgent need to understand the workings of the parasite at a molecular level to enable the development of alternative antimalarial strategies. During part of its life cycle, the malaria parasite infects the erythrocytes of its human host. The parasite transports proteins to the erythrocyte membrane so as to modify the properties of its adopted cellular residence. The parasite proteins that are deposited at or in the erythrocyte membrane increase the leakiness and the stickiness of the parasitised erythrocytes. This allows more efficient uptake of nutrients and allows the parasitised erythrocytes to adhere to blood vessel walls, thereby avoiding passage through the spleen. Adherence of parasitised erythrocytes to capillaries in the brain is thought to lead to the development of the complication known as cerebral malaria. This complication is responsible for most of the deaths due to malaria. In order to traffic the adherence proteins to the erythrocyte surface, the parasite establishes a novel transport pathway for moving proteins across the erythrocyte cytoplasm. As the uninfected erythrocyte has no means, nor requirement, for moving proteins, this novel transport mechanism may represent a target for drugs that kill the malaria parasite without being toxic to humans. The pathways for the movement of proteins around the infected erythrocyte are largely unknown. We propose to use techniques to introduce foreign genes into malaria-infected erythrocytes to unravel the details of the molecular machinery and the ticketing system that the parasite uses to traffic proteins to their correct destinations in its adopted home.Read moreRead less
Protein Trafficking In Malaria Parasite-infected Erythrocytes
Funder
National Health and Medical Research Council
Funding Amount
$417,750.00
Summary
Malaria kills between 1 and 3 million children each year. In addition, the disease debilitates the adult population in malaria-endemic areas, thereby contributing to the cycle of poverty in many third world countries. As resistance to existing antimalarial drugs increases, there is an urgent need to understand the workings of the parasite at a molecular level to enable the development of alternative antimalarial strategies. During part of its life cycle, the malaria parasite infects the erythroc ....Malaria kills between 1 and 3 million children each year. In addition, the disease debilitates the adult population in malaria-endemic areas, thereby contributing to the cycle of poverty in many third world countries. As resistance to existing antimalarial drugs increases, there is an urgent need to understand the workings of the parasite at a molecular level to enable the development of alternative antimalarial strategies. During part of its life cycle, the malaria parasite infects the erythrocytes of its human host. The parasite transports proteins to the erythrocyte membrane so as to modify the properties of its adopted cellular residence. The parasite proteins that are deposited at or in the erythrocyte membrane increase the leakiness and the stickiness of the parasitised erythrocytes. This allows more efficient uptake of nutrients and allows the parasitised erythrocytes to adhere to blood vessel walls, thereby avoiding passage through the spleen. Adherence of parasitised erythrocytes to capillaries in the brain is thought to lead to the development of the complication known as cerebral malaria. This complication is responsible for most of the deaths due to malaria. In order to traffic the adherence proteins to the erythrocyte surface, the parasite establishes novel transport pathways for moving proteins across the erythrocyte cytoplasm. As the uninfected erythrocyte has no means, nor requirement, for moving proteins, this novel transport mechanism may represent a target for drugs that kill the malaria parasite without being toxic to humans. The pathways for the movement of proteins around the infected erythrocyte are largely unknown. We propose to use cell biology techniques and techniques to introduce foreign genes into malaria-infected erythrocytes to unravel the details of the molecular machinery and the ticketing system that the parasite uses to traffic proteins to their correct destinations in its adopted home.Read moreRead less