The normal functioning of many organs is controlled by several types of nerves through releasing chemicals called neurotransmitters. A new type of nerve has been identified recently; these are called nitrergic nerves. They release a nitric oxide-like transmitter to control the relaxation of smooth muscle. Although it is known that nitrergic nerves play important roles in the regulation of functions of various organs, the nature of its transmitter has not been elucidated. Our recent study suggest ....The normal functioning of many organs is controlled by several types of nerves through releasing chemicals called neurotransmitters. A new type of nerve has been identified recently; these are called nitrergic nerves. They release a nitric oxide-like transmitter to control the relaxation of smooth muscle. Although it is known that nitrergic nerves play important roles in the regulation of functions of various organs, the nature of its transmitter has not been elucidated. Our recent study suggests that the nitrergic transmitter is more close to a redox form of nitric oxide such as nitroxyl anion than to nitric oxide itself. This project will investigate further the mechanism of nitrergic transmission including the nature of the nitrergic transmitter. The proposed research will help to answer important questions regarding the mechanisms of nitrergic transmission and thus may throw additional light to the nature of the nitrergic transmitter. The findings may also be significant for the development of new drugs (such as new NO donors) which interact with nitrergic mechanisms.Read moreRead less
Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from synaptic vesicles inside nerve endings (exocytosis) and the recycling of those synaptic vesicles (endocytosis). These events are mainly controlled by a large number of synapse-specific proteins, and partly regulated by a signalling molecule, cGMP, w ....Nerve cells have unique properties like their ability to put out axons that reach long distances from the cell body (differentiation), their ability to make contacts with other cells and initiate communication by the release of neurotransmitters from synaptic vesicles inside nerve endings (exocytosis) and the recycling of those synaptic vesicles (endocytosis). These events are mainly controlled by a large number of synapse-specific proteins, and partly regulated by a signalling molecule, cGMP, which mainly stimulates the enzyme PKG. In previous studies supported by the NHMRC we identified many proteins that are phosphorylated and activated by PKG. One of them, septin 3, is the focus of this proposal. We initially cloned septin 3 as a new member of a family of 10 genes that are essential for cell division. Some septins assemble as filaments that allow the two new daughter cells to finally separate. When the filament formation is perturbed certain septins end up in microscopic clumps that are found in the post-mortem brains of people affected by Alzheimer's disease, suggesting they might contribute to the disease. However, septin 3 is unlike most septins because it is a brain-specific septin, which we found in neurons and found to be highly concentrated in nerve terminals, locations not normally associated with cell division. The only other known brain-specific septin, CDCrel-1, regulates the protein machinery of exocytosis. We will examine the hypothesis that G-septin is also a regulator of synaptic vesicle endocytosis. We will determine whether septin represents a convergence point for cGMP signalling to control endocytosis. A better understanding of septin 3 and endocytosis is crucial to understanding brain disorders and ultimately developing better therapies.Read moreRead less
The Function Of Dynamin Phosphorylation Sites In Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$794,565.00
Summary
Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when ....Neurons communicate with each other via the release of neurotransmitters which are packaged in synaptic vesicles inside nerve endings. There are a finite number of vesicles, so they are recycled (endocytosis) for reuse. Synaptic vesicle exocytosis is very fast and normally endocytosis is a little slower, mopping up the used vesicles. Recently we showed that endocytosis can control synaptic transmission, hence it's an integral part of an overall cycle of synaptic transmission. We found that when endocytosis cannot keep up then exocytosis slows, greatly reducing the function of neurons. A complete block would result in paralysis of brain and muscles. Our team has been revealing the underlying molecular mechanisms of endocytosis in order to better understand diseases of the synapse like schizophrenia, epilepsy and Alzheimer's disease. We discovered that endocytosis is a regulated process at the heart of which is a pair of phosphorylation sites (points of phosphate attachment) in the key protein dynamin I. Our hypothesis is that endocytosis occurs in two forms, fast and slow. We propose to test the idea that proteins that associate with dynamin via the phosphorylation sites determine whether the fast or slow mode is used. Additionally, we propose that the first phosphorylation site is the trigger for endocytosis, while the second serves to recruit reserve supplies of dynamin to support the slow mode when it's required. A better understanding of Dyn and endocytosis is crucial to understanding brain disorders of synaptic transmission and ultimately for developing therapies. For example, a seizure is the uncontrolled firing of neurons. Our overall aim is to understand the control mechanisms of nerve communication to ultimately allow us to treat disorders of nerve communication like epilepsy.Read moreRead less
Role Of Dynamin In Modes Of Synaptic Vesicle Endocytosis
Funder
National Health and Medical Research Council
Funding Amount
$905,985.00
Summary
Neurons communicate by neurotransmitter release from synaptic vesicles stored in nerve endings. There is a finite vesicle number, so they are recycled (endocytosis) by dynamin. Our aim is to reveal the molecular mechanisms underlying endocytosis to better understand diseases of the synapse like epilepsy. We propose that two forms of the dynamin gene mediate two forms of endocytosis, one of which is activated only under conditions of high neuronal firing, such as occurs during a seizure.
Central pathways regulating visceral pain. This project aims to investigate the neural pathways within the spinal cord and brain processing colorectal pain perception. The project aims to identify the spinal cord neurons relaying colorectal signalling into the brain and the influence of descending modulation from the brainstem upon these pathways. The outcomes will greatly benefit fundamental understanding of the central pathways processing visceral pain.
Transcriptional control of neural stem cell differentiation during development and disease. Understanding the molecular mechanisms that control how neural stem cells differentiate is critical to provide potential therapeutic treatment for neurodegenerative diseases and for brain cancer. This project will aim to discover, using an animal model system, the genes and molecules regulating these key biological processes.
Linkage Infrastructure, Equipment And Facilities - Grant ID: LE100100074
Funder
Australian Research Council
Funding Amount
$520,000.00
Summary
Facilities for automated high-throughput slide scanning and stereology. The equipment requested will facilitate the work of the Australian Mouse Brain Mapping Consortium, a consortium of Australian research groups collaborating to provide the only mouse model brain mapping capability in the country. The consortium brings together laboratory, neuroimaging and computational expertise in a comprehensive framework for imaging the mouse brain. This will help researchers to study mouse models of genet ....Facilities for automated high-throughput slide scanning and stereology. The equipment requested will facilitate the work of the Australian Mouse Brain Mapping Consortium, a consortium of Australian research groups collaborating to provide the only mouse model brain mapping capability in the country. The consortium brings together laboratory, neuroimaging and computational expertise in a comprehensive framework for imaging the mouse brain. This will help researchers to study mouse models of genetic and acquired disorders across the life-span. Remote viewing and analysis capabilities will help overcome the 'tyranny of distance', increasing national access to the facility. Repositories of digitised images will increase the availability of valuable research material to other Australian and international researchers.Read moreRead less
Regulation of neuronal cell death signalling for the treatment of neurodegenerative diseases. The progression of neurodegenerative diseases, such as Alzheimer's and motor neuron diseases, are often underpinned by neuronal cell death-signalling. This project aims to characterise molecules that regulate cell death signalling, thereby increasing our knowledge of how neuronal cell death can be inhibited.
Discovery Early Career Researcher Award - Grant ID: DE130100323
Funder
Australian Research Council
Funding Amount
$375,000.00
Summary
The regulation by transcription factor phosphorylation upon the myelinating process. The project will investigate the novel molecular events that control the myelinating process, which is essential for normal nervous system function. Outcomes of this project may aid the development of novel interventions to improve control of demyelinating diseases, which represent a substantial socio-economic burden.
Psychiatric disorders in epilepsy. Psychiatric disorders, such as depression, anxiety and cognitive disorders, are frequently observed in patients with epilepsy. Although standard dogma suggests that psychiatric disorders are a consequence of living with epilepsy, recent evidence suggests a bidirectional relationship between these disorders, such that depression and other psychiatric illnesses act as risk factors for epilepsy development. This project will utilise basic science approaches to und ....Psychiatric disorders in epilepsy. Psychiatric disorders, such as depression, anxiety and cognitive disorders, are frequently observed in patients with epilepsy. Although standard dogma suggests that psychiatric disorders are a consequence of living with epilepsy, recent evidence suggests a bidirectional relationship between these disorders, such that depression and other psychiatric illnesses act as risk factors for epilepsy development. This project will utilise basic science approaches to understand the causal relationships between epilepsy and psychiatric disorders, and determine how and why psychiatric disorders and epilepsy co-exist. It is hoped that research conducted in this project will develop novel avenues to treatment of both epilepsy and psychiatric disorders.Read moreRead less